Simulations of extensional flow in microrheometric devices

We present a detailed numerical study of the flow of a Newtonian fluid through microrheometric devices featuring a sudden contraction–expansion. This flow configuration is typically used to generate extensional deformations and high strain rates. The excess pressure drop resulting from the converging and diverging flow is an important dynamic measure to quantify if the device is intended to be used as a microfluidic extensional rheometer. To explore this idea, we examine the effect of the contraction length, aspect ratio and Reynolds number on the flow kinematics and resulting pressure field. Analysis of the computed velocity and pressure fields show that, for typical experimental conditions used in microfluidic devices, the steady flow is highly three-dimensional with open spiraling vortical structures in the stagnant corner regions. The numerical simulations of the local kinematics and global pressure drop are in good agreement with experimental results. The device aspect ratio is shown to have a strong impact on the flow and consequently on the excess pressure drop, which is quantified in terms of the dimensionless Couette and Bagley correction factors. We suggest an approach for calculating the Bagley correction which may be especially appropriate for planar microchannels

International Veterinary Epilepsy Task Force consensus proposal: Medical treatment of canine epilepsy in Europe

In Europe, the number of antiepileptic drugs (AEDs) licensed for dogs has grown considerably over the last years. Nevertheless, the same questions remain, which include, 1) when to start treatment, 2) which drug is best used initially, 3) which adjunctive AED can be advised if treatment with the initial drug is unsatisfactory, and 4) when treatment changes should be considered. In this consensus proposal, an overview is given on the aim of AED treatment, when to start long-term treatment in canine epilepsy and which veterinary AEDs are currently in use for dogs. The consensus proposal for drug treatment protocols, 1) is based on current published evidence-based literature, 2) considers the current legal framework of the cascade regulation for the prescription of veterinary drugs in Europe, and 3) reflects the authors’ experience. With this paper it is aimed to provide a consensus for the management of canine idiopathic epilepsy. Furthermore, for the management of structural epilepsy AEDs are inevitable in addition to treating the underlying cause, if possible

Lymphatic vessel density and VEGF-C expression are significantly different among benign and malignant thyroid lesions

Thyroid cancer is the most frequent endocrine neoplasia worldwide. The route for metastasis and loco-regional invasion preferentially occurs by lymphatic vessels. For this reason, the assessment of lymphatic vessel density (LVD) is supposed to represent both a prognostic parameter and also a potential therapeutic target. In order to evaluate the value of LVD in benign and malignant thyroid lesions, we analyzed 110 thyroidectomy specimens using D2-40, a specific marker for lymphatic vessels and vascular endothelial growth factor C (VEGF-C), the most potent molecule of lymphatic proliferation. LVD was significantly different between papillary and follicular carcinomas in total (p = 0.045) and peritumoral area (p = 0.042). Follicular adenoma and follicular carcinoma showed an important difference of intra- (p = 0.019) and peritumoral (p = 0.033) LVD. VEGF-C was more markedly expressed in malignancies than in benign lesions (p = 0.0001). Almost all cancers with high positive VEGF-C expression also exhibited increased peritumoral LVD (p = 0.049) when compared with the benign lesions. Indeed, the high peritumoral LVD of malignant thyroid lesions is an important finding for surgery planning and supports the practice of total thyroidectomy in malignant thyroid neoplasm's since the lymphatic peritumoral vessels definitely are an escape path for tumor cells

f(R) theories

Over the past decade, f(R) theories have been extensively studied as one of the simplest modifications to General Relativity. In this article we review various applications of f(R) theories to cosmology and gravity - such as inflation, dark energy, local gravity constraints, cosmological perturbations, and spherically symmetric solutions in weak and strong gravitational backgrounds. We present a number of ways to distinguish those theories from General Relativity observationally and experimentally. We also discuss the extension to other modified gravity theories such as Brans-Dicke theory and Gauss-Bonnet gravity, and address models that can satisfy both cosmological and local gravity constraints.Comment: 156 pages, 14 figures, Invited review article in Living Reviews in Relativity, Published version, Comments are welcom

Efficacy and Safety of AmBisome in Combination with Sodium Stibogluconate or Miltefosine and Miltefosine Monotherapy for African Visceral Leishmaniasis: Phase II Randomized Trial.

BACKGROUND: SSG&PM over 17 days is recommended as first line treatment for visceral leishmaniasis in eastern Africa, but is painful and requires hospitalization. Combination regimens including AmBisome and miltefosine are safe and effective in India, but there are no published data from trials of combination therapies including these drugs from Africa. METHODS: A phase II open-label, non-comparative randomized trial was conducted in Sudan and Kenya to evaluate the efficacy and safety of three treatment regimens: 10 mg/kg single dose AmBisome plus 10 days of SSG (20 mg/kg/day), 10 mg/kg single dose AmBisome plus 10 days of miltefosine (2.5mg/kg/day) and miltefosine alone (2.5 mg/kg/day for 28 days). The primary endpoint was initial parasitological cure at Day 28, and secondary endpoints included definitive cure at Day 210, and pharmacokinetic (miltefosine) and pharmacodynamic assessments. RESULTS: In sequential analyses with 49-51 patients per arm, initial cure was 85% (95% CI: 73-92) in all arms. At D210, definitive cure was 87% (95% CI: 77-97) for AmBisome + SSG, 77% (95% CI 64-90) for AmBisome + miltefosine and 72% (95% CI 60-85) for miltefosine alone, with lower efficacy in younger patients, who weigh less. Miltefosine pharmacokinetic data indicated under-exposure in children compared to adults. CONCLUSION: No major safety concerns were identified, but point estimates of definitive cure were less than 90% for each regimen so none will be evaluated in Phase III trials in their current form. Allometric dosing of miltefosine in children needs to be evaluated. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov, number NCT01067443

An assessment of upper ocean salinity content from the ocean reanalyses inter-comparison project (ORA-IP)

Many institutions worldwide have developed ocean reanalyses systems (ORAs) utilizing a variety of ocean models and assimilation techniques. However, the quality of salinity reanalyses arising from the various ORAs has not yet been comprehensively assessed. In this study, we assess the upper ocean salinity content (depth-averaged over 0–700 m) from 14 ORAs and 3 objective ocean analysis systems (OOAs) as part of the Ocean Reanalyses Intercomparison Project. Our results show that the best agreement between estimates of salinity from different ORAs is obtained in the tropical Pacific, likely due to relatively abundant atmospheric and oceanic observations in this region. The largest disagreement in salinity reanalyses is in the Southern Ocean along the Antarctic circumpolar current as a consequence of the sparseness of both atmospheric and oceanic observations in this region. The West Pacific warm pool is the largest region where the signal to noise ratio of reanalysed salinity anomalies is >1. Therefore, the current salinity reanalyses in the tropical Pacific Ocean may be more reliable than those in the Southern Ocean and regions along the western boundary currents. Moreover, we found that the assimilation of salinity in ocean regions with relatively strong ocean fronts is still a common problem as seen in most ORAs. The impact of the Argo data on the salinity reanalyses is visible, especially within the upper 500m, where the interannual variability is large. The increasing trend in global-averaged salinity anomalies can only be found within the top 0–300m layer, but with quite large diversity among different ORAs. Beneath the 300m depth, the global-averaged salinity anomalies from most ORAs switch their trends from a slightly growing trend before 2002 to a decreasing trend after 2002. The rapid switch in the trend is most likely an artefact of the dramatic change in the observing system due to the implementation of Argo

Antibiotic prescribing for upper respiratory infections among children in rural China: a cross-sectional study of outpatient prescriptions

Background: Overuse of antibiotics contributes to the development of antimicrobial resistance. Objective: This study aims to assess the condition of antibiotic use at health facilities at county, township and village levels in rural Guangxi, China. Methods: We conducted a cross-sectional study of outpatient antibiotic prescriptions in 2014 for children aged 2–14 years with upper respiratory infections (URI). Twenty health facilities were randomly selected, including four county hospitals, eight township hospitals and eight village clinics. Prescriptions were extracted from the electronic records in the county hospitals and paper copies in the township hospitals and village clinics. Results: The antibiotic prescription rate was higher in township hospitals (593/877, 68%) compared to county hospitals (2736/8166, 34%) and village clinics (96/297, 32%) (p < 0.001). Among prescriptions containing antibiotics, county hospitals were found to have the highest use rate of broad-spectrum antibiotics (82 vs 57% [township], vs 54% [village], p < 0.001), injectable antibiotics (65 vs 43% [township], vs 33% [village], p < 0.001) and multiple antibiotics (47 vs 15% [township], vs 0% [village], p < 0.001). Logistic regression showed that the likelihood of prescribing an antibiotic was significantly associated with patients being 6–14 years old compared with being 2–5 years old (adjusted odds ratio [aOR] = 1.3, 95% CI 1.2–1.5), and receiving care at township hospitals compared with county hospitals (aOR = 5.0, 95% CI 4.1–6.0). Prescriptions with insurance copayment appeared to lower the risk of prescribing antibiotics compared with those without (aOR = 0.8, 95% CI 0.7–0.9). Conclusions: Inappropriate use of antibiotics was high for outpatient childhood URI in the four counties of Guangxi, China, with the highest rate found in township hospitals. A significant high proportion of prescriptions containing antibiotics were broad-spectrum, by intravenous infusion or with multiple antibiotics, especially at county hospitals. Urgent attention is needed to address this challenge

Single-cell RNA-sequencing resolves self-antigen expression during mTEC development

The crucial capability of T cells for discrimination between self and non-self peptides is based on negative selection of developing thymocytes by medullary thymic epithelial cells (mTECs). The mTECs purge autoreactive T cells by expression of cell-type specific genes referred to as tissue-restricted antigens (TRAs). Although the autoimmune regulator (AIRE) protein is known to promote the expression of a subset of TRAs, its mechanism of action is still not fully understood. The expression of TRAs that are not under the control of AIRE also needs further characterization. Furthermore, expression patterns of TRA genes have been suggested to change over the course of mTEC development. Herein we have used single-cell RNA-sequencing to resolve patterns of TRA expression during mTEC development. Our data indicated that mTEC development consists of three distinct stages, correlating with previously described jTEC, mTEChi and mTEClo phenotypes. For each subpopulation, we have identified marker genes useful in future studies. Aire-induced TRAs were switched on during jTEC-mTEC transition and were expressed in genomic clusters, while otherwise the subsets expressed largely overlapping sets of TRAs. Moreover, population-level analysis of TRA expression frequencies suggested that such differences might not be necessary to achieve efficient thymocyte selection.RM is supported by a PhD Fellowship from the Fundação para a Ciência e Tecnologia, Portugal (SFRH/ BD/51950/2012). XZ is supported by an Advanced Postdoc Mobility Fellowship from the Swiss National Science Foundation (SNSF, grant number P300P2_151352). Part of the work was performed during XZ’s visit to the Simons Institute for the Theory of Computing. TL is supported by the Academy of Finland (Decision 311081). The authors would like to thank Bee Ling Ng and the staff of the Cytometry Core Facility, and Stephan Lorenz and the staff of the Single Cell Genomics Core Facility for their contribution. Mark Lynch is acknowledged for technical assistance with the Fluidigm C1 platform. Mike Stubbington and Kylie James are acknowledged for revising the language of the manuscript. We thank Sarah Teichmann for help and discussions regarding the manuscript.info:eu-repo/semantics/publishedVersio

RAId_aPS: MS/MS analysis with multiple scoring functions and spectrum-specific statistics

Statistically meaningful comparison/combination of peptide identification results from various search methods is impeded by the lack of a universal statistical standard. Providing an E-value calibration protocol, we demonstrated earlier the feasibility of translating either the score or heuristic E-value reported by any method into the textbook-defined E-value, which may serve as the universal statistical standard. This protocol, although robust, may lose spectrum-specific statistics and might require a new calibration when changes in experimental setup occur. To mitigate these issues, we developed a new MS/MS search tool, RAId_aPS, that is able to provide spectrum-specific E-values for additive scoring functions. Given a selection of scoring functions out of RAId score, K-score, Hyperscore and XCorr, RAId_aPS generates the corresponding score histograms of all possible peptides using dynamic programming. Using these score histograms to assign E-values enables a calibration-free protocol for accurate significance assignment for each scoring function. RAId_aPS features four different modes: (i) compute the total number of possible peptides for a given molecular mass range, (ii) generate the score histogram given a MS/MS spectrum and a scoring function, (iii) reassign E-values for a list of candidate peptides given a MS/MS spectrum and the scoring functions chosen, and (iv) perform database searches using selected scoring functions. In modes (iii) and (iv), RAId_aPS is also capable of combining results from different scoring functions using spectrum-specific statistics. The web link is http://www.ncbi.nlm.nih.gov/CBBresearch/Yu/raid_aps/index.html. Relevant binaries for Linux, Windows, and Mac OS X are available from the same page.Comment: 34 pages, 10 figures, 1 supplementary information file (RAId_aPS_support.pdf). To view the supplementary file, please download and extract the gzipped tar source file listed under "Other formats