Efficacy and safety of discontinuing antibiotic treatment for uncomplicated respiratory tract infections when deemed unnecessary. A multicentre, randomized clinical trial in primary care

Antibacterial agent; Antibiotic stewardship; Primary health careAgente antibacteriano; Administración de antibióticos; Atención primaria de saludAgent antibacterià; Administració d'antibiòtics; Atenció primària de salutObjectives To determine the benefits and harms of discontinuing unnecessary antibiotic therapy for uncomplicated respiratory tract infections (RTI) when antibiotics are considered no longer necessary. Methods Multicentre, open-label, randomized controlled clinical trial in primary care centres from 2017 to 2020 (ClinicalTrials.gov, NCT02900820). Adults with RTIs—acute rhinosinusitis, sore throat, influenza or acute bronchitis—who had previously taken any dose of antibiotic for less than 3 days, which physicians no longer deemed necessary were recruited. The patients were randomly assigned in a 1:1 ratio to discontinuing antibiotic therapy or the usual strategy of continuing antibiotic treatment. The primary outcome was the duration of severe symptoms (number of days scoring 5 or 6 on a six-item Likert scale). Secondary outcomes included days with symptoms, moderate symptoms (scores of 3 or 4), antibiotics taken, adverse events, patient satisfaction and complications within the first 3 months. Results A total of 467 patients were randomized, out of which 409 were considered valid for the analysis. The mean (SD) duration of severe symptoms was 3.0 (1.5) days for the patients assigned to discontinuation and 2.8 (1.3) days for those allocated to the control group (mean difference 0.2 days; 95% CI –0.1 to 0.4 days). Patients randomized to the discontinuation group used fewer antibiotics after the baseline visit (52/207 (25.1%) versus 182/202 (90.1%); p 0.001). Patients assigned to antibiotic continuation presented a relative risk of adverse events of 1.47 (95% CI 0.80–2.71), but the need for further health-care contact in the following 3 months was slightly lower (RR 0.61; 95% CI 0.28–1.37). Conclusions Discontinuing antibiotic treatment for uncomplicated RTIs when clinicians consider it unnecessary is safe and notably reduces antibiotic consumption.This work was supported by the Catalan Society of Family Medicine, grant number FAP1601. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. This trial was registered with the ClinicalTrials.gov database (Identifier: NCT02900820)

Chemical abundance gradients from open clusters in the Milky Way disk: results from the APOGEE survey

Metallicity gradients provide strong constraints for understanding the chemical evolution of the Galaxy. We report on radial abundance gradients of Fe, Ni, Ca, Si, and Mg obtained from a sample of 304 red-giant members of 29 disk open clusters, mostly concentrated at galactocentric distances between ~8 - 15 kpc, but including two open clusters in the outer disk. The observations are from the APOGEE survey. The chemical abundances were derived automatically by the ASPCAP pipeline and these are part of the SDSS III Data Release 12. The gradients, obtained from least squares fits to the data, are relatively flat, with slopes ranging from -0.026 to -0.033 dex/kpc for the alpha-elements [O/H], [Ca/H], [Si/H] and [Mg/H] and -0.035 dex/kpc and -0.040 dex/kpc for [Fe/H] and [Ni/H], respectively. Our results are not at odds with the possibility that metallicity ([Fe/H]) gradients are steeper in the inner disk (R_GC ~7 - 12 kpc) and flatter towards the outer disk. The open cluster sample studied spans a significant range in age. When breaking the sample into age bins, there is some indication that the younger open cluster population in our sample (log age < 8.7) has a flatter metallicity gradient when compared with the gradients obtained from older open clusters.Comment: 4 pages, 3 figures, To appear in Astronomische Nachrichten, special issue "Reconstruction the Milky Way's History: Spectroscopic surveys, Asteroseismology and Chemo-dynamical models", Guest Editors C. Chiappini, J. Montalb\'an, and M. Steffen, AN 2016 (in press)

Functional mammalian spliceosomal complex E contains SMN complex proteins in addition to U1 and U2 snRNPs

Copyright @ 2011 The Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Spliceosomes remove introns from primary gene transcripts. They assemble de novo on each intron through a series of steps that involve the incorporation of five snRNP particles and multiple non-snRNP proteins. In mammals, all the intermediate complexes have been characterized on one transcript (MINX), with the exception of the very first, complex E. We have purified this complex by two independent procedures using antibodies to either U1-A or PRPF40A proteins, which are known to associate at an early stage of assembly. We demonstrate that the purified complexes are functional in splicing using commitment assays. These complexes contain components expected to be in the E complex and a number of previously unrecognized factors, including survival of motor neurons (SMN) and proteins of the SMN-associated complex. Depletion of the SMN complex proteins from nuclear extracts inhibits formation of the E complex and causes non-productive complexes to accumulate. This suggests that the SMN complex stabilizes the association of U1 and U2 snRNPs with pre-mRNA. In addition, the antibody to PRPF40A precipitated U2 snRNPs from nuclear extracts, indicating that PRPF40A associates with U2 snRNPs

Isoforms of U1-70k control subunit dynamics in the human spliceosomal U1 snRNP

Most human protein-encoding genes contain multiple exons that are spliced together, frequently in alternative arrangements, by the spliceosome. It is established that U1 snRNP is an essential component of the spliceosome, in human consisting of RNA and ten proteins, several of which are post- translationally modified and exist as multiple isoforms. Unresolved and challenging to investigate are the effects of these post translational modifications on the dynamics, interactions and stability of the particle. Using mass spectrometry we investigate the composition and dynamics of the native human U1 snRNP and compare native and recombinant complexes to isolate the effects of various subunits and isoforms on the overall stability. Our data reveal differential incorporation of four protein isoforms and dynamic interactions of subunits U1-A, U1-C and Sm-B/B’. Results also show that unstructured post- ranslationally modified C-terminal tails are responsible for the dynamics of Sm-B/B’ and U1-C and that their interactions with the Sm core are controlled by binding to different U1-70k isoforms and their phosphorylation status in vivo. These results therefore provide the important functional link between proteomics and structure as well as insight into the dynamic quaternary structure of the native U1 snRNP important for its function.This work was funded by: BBSRC (OVM), BBSRC and EPSRC (HH and NM), EU Prospects (HH), European Science Foundation (NM), the Royal Society (CVR), and fellowship from JSPS and HFSP (YM and DAPK respectively)

Shoc2/Sur8 protein regulates neurite outgrowth

This is an openaccess article distributed under the terms of the Creative Commons Attribution License.-- et al.The Shoc2 protein has been implicated in the positive regulation of the Ras-ERK pathway by increasing the functional binding interaction between Ras and Raf, leading to increased ERK activity. Here we found that Shoc2 overexpression induced sustained ERK phosphorylation, notably in the case of EGF stimulation, and Shoc2 knockdown inhibited ERK activation. We demonstrate that ectopic overexpression of human Shoc2 in PC12 cells significantly promotes neurite extension in the presence of EGF, a stimulus that induces proliferation rather than differentiation in these cells. Finally, Shoc2 depletion reduces both NGF-induced neurite outgrowth and ERK activation in PC12 cells. Our data indicate that Shoc2 is essential to modulate the Ras-ERK signaling outcome in cell differentiation processes involved in neurite outgrowth.GL, TG and LMD were recipients of fellowships from the Ministerio de Educación y Ciencia (MEC) (to GL, TG), and Fondo de Investigaciones Sanitarias (FIS) (to LMD). LSR held a postdoctoral research contract from CIBERNED. This work was supported by FIS grant (PI10/00815) to JLO; CIBERNED to MC; SAF2008-01951, Comunidad Autónoma de Madrid (CAM) SSAL-0202-2006-01 and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) to TI; FIS grant PI12/00775 and ISCIII-RETIC (Red Temática de Investigación Cooperativa en Cáncer) RD12/0036/0027 from the Instituto de Salud Carlos III to PSG; and FIS grants (PI09/0562 and PI13/00703), ISCIIIRETIC (RD06/0020/0003 and RD12/0036/0021), and the Spanish Association Against Cancer (AECC) to JMR.Peer Reviewe

Towards a consistent mechanism of emulsion polymerization—new experimental details

The application of atypical experimental methods such as conductivity measurements, optical microscopy, and nonstirred polymerizations to investigations of the ‘classical’ batch ab initio emulsion polymerization of styrene revealed astonishing facts. The most important result is the discovery of spontaneous emulsification leading to monomer droplets even in the quiescent styrene in water system. These monomer droplets with a size between a few and some hundreds of nanometers, which are formed by spontaneous emulsification as soon as styrene and water are brought into contact, have a strong influence on the particle nucleation, the particle morphology, and the swelling of the particles. Experimental results confirm that micelles of low-molecular-weight surfactants are not a major locus of particle nucleation. Brownian dynamics simulations show that the capture of matter by the particles strongly depends on the polymer volume fraction and the size of the captured species (primary free radicals, oligomers, single monomer molecules, or clusters)

Drugst.One -- A plug-and-play solution for online systems medicine and network-based drug repurposing

In recent decades, the development of new drugs has become increasingly expensive and inefficient, and the molecular mechanisms of most pharmaceuticals remain poorly understood. In response, computational systems and network medicine tools have emerged to identify potential drug repurposing candidates. However, these tools often require complex installation and lack intuitive visual network mining capabilities. To tackle these challenges, we introduce Drugst.One, a platform that assists specialized computational medicine tools in becoming user-friendly, web-based utilities for drug repurposing. With just three lines of code, Drugst.One turns any systems biology software into an interactive web tool for modeling and analyzing complex protein-drug-disease networks. Demonstrating its broad adaptability, Drugst.One has been successfully integrated with 21 computational systems medicine tools. Available at https://drugst.one, Drugst.One has significant potential for streamlining the drug discovery process, allowing researchers to focus on essential aspects of pharmaceutical treatment research.Comment: 45 pages, 6 figures, 7 table

Oscillation Physics with a Neutrino Factory

A generation of neutrino experiments have established that neutrinos mix and probably have mass. The mixing phenomenon points to processes beyond those of the Standard Model, possibly at the Grand Unification energy scale. A extensive sequence of of experiments will be required to measure precisely all the parameters of the neutrino mixing matrix, culminating with the discovery and study of leptonic CP violation. As a first step, extensions of conventional pion/kaon decay beams, such as off-axis beams or low-energy super-beams, have been considered. These could yield first observations of $\nu_\mu \to \nu_e$ transitions at the atmospheric frequency, which have not yet been observed, and a first measurement of $\theta_{13}$. Experiments with much better flux control can be envisaged if the neutrinos are obtained from the decays of stored particles. One such possibility is the concept of beta beams provided by the decays of radioactive nuclei, that has been developed within the context of these studies. These would provide a pure (anti-)electron-neutrino beam of a few hundred MeV, and beautiful complementarity with a high-intensity, low-energy conventional beam, enabling experimental probes of T violation as well as CP violation. Ultimately, a definitive and complete set of measurements would offered by a Neutrino Factory based on a muon storage ring. This powerful machine offers the largest reach for CP violation, even for very small values of $\theta_{13}$

Gene Expression and Functional Studies of the Optic Nerve Head Astrocyte Transcriptome from Normal African Americans and Caucasian Americans Donors

To determine whether optic nerve head (ONH) astrocytes, a key cellular component of glaucomatous neuropathy, exhibit differential gene expression in primary cultures of astrocytes from normal African American (AA) donors compared to astrocytes from normal Caucasian American (CA) donors.We used oligonucleotide Affymetrix microarray (HG U133A & HG U133A 2.0 chips) to compare gene expression levels in cultured ONH astrocytes from twelve CA and twelve AA normal age matched donor eyes. Chips were normalized with Robust Microarray Analysis (RMA) in R using Bioconductor. Significant differential gene expression levels were detected using mixed effects modeling and Statistical Analysis of Microarray (SAM). Functional analysis and Gene Ontology were used to classify differentially expressed genes. Differential gene expression was validated by quantitative real time RT-PCR. Protein levels were detected by Western blots and ELISA. Cell adhesion and migration assays tested physiological responses. Glutathione (GSH) assay detected levels of intracellular GSH.Multiple analyses selected 87 genes differentially expressed between normal AA and CA (P<0.01). The most relevant genes expressed in AA were categorized by function, including: signal transduction, response to stress, ECM genes, migration and cell adhesion.These data show that normal astrocytes from AA and CA normal donors display distinct expression profiles that impact astrocyte functions in the ONH. Our data suggests that differences in gene expression in ONH astrocytes may be specific to the development and/or progression of glaucoma in AA