Contact transmission of influenza virus between ferrets imposes a looser bottleneck than respiratory droplet transmission allowing propagation of antiviral resistance

Influenza viruses cause annual seasonal epidemics and occasional pandemics. It is important to elucidate the stringency of bottlenecks during transmission to shed light on mechanisms that underlie the evolution and propagation of antigenic drift, host range switching or drug resistance. The virus spreads between people by different routes, including through the air in droplets and aerosols, and by direct contact. By housing ferrets under different conditions, it is possible to mimic various routes of transmission. Here, we inoculated donor animals with a mixture of two viruses whose genomes differed by one or two reverse engineered synonymous mutations, and measured the transmission of the mixture to exposed sentinel animals. Transmission through the air imposed a tight bottleneck since most recipient animals became infected by only one virus. In contrast, a direct contact transmission chain propagated a mixture of viruses suggesting the dose transferred by this route was higher. From animals with a mixed infection of viruses that were resistant and sensitive to the antiviral drug oseltamivir, resistance was propagated through contact transmission but not by air. These data imply that transmission events with a looser bottleneck can propagate minority variants and may be an important route for influenza evolution

On the Use of Iterative Approximations in Queueing Networks; with Simple Applications

Networks of queues which have a productform solution can be analyzed easily by the convolution method or with mean value analysis. Regrettably, however, many practical queueing network models do not possess a productform solution. In this paper the following approach is advocated for models with alight deviations from the productform conditions: approximate the model interatively by a sequence of models which satisfy conditions for simple analysis. Quite often aggregation and mean value analysis provide the natural approach for de signing an iteration step. Applications which are mentioned are: two-phase servers where the first phase is a preparatory one; a type of priorities; blocking; many-chains networks; FCFS-servers with different workloads for different types of customers

Host Species Restriction of Middle East Respiratory Syndrome Coronavirus through Its Receptor, Dipeptidyl Peptidase 4

Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012. Recently, the MERS-CoV receptor dipeptidyl peptidase 4 (DPP4) was identified and the specific interaction of the receptor-binding domain (RBD) of MERS-CoV spike protein and DPP4 was determined by crystallography. Animal studies identified rhesus macaques but not hamsters, ferrets, or mice to be susceptible for MERS-CoV. Here, we investigated the role of DPP4 in this observed species tropism. Cell lines of human and nonhuman primate origin were permissive of MERS-CoV, whereas hamster, ferret, or mouse cell lines were not, despite the presence of DPP4. Expression of human DPP4 in nonsusceptible BHK and ferret cells enabled MERS-CoV replication, whereas expression of hamster or ferret DPP4 did not. Modeling the binding energies of MERS-CoV spike protein RBD to DPP4 of human (susceptible) or hamster (nonsusceptible) identified five amino acid residues involved in the DPP4-RBD interaction. Expression of hamster DPP4 containing the five human DPP4 amino acids rendered BHK cells susceptible to MERS-CoV, whereas expression of human DPP4 containing the five hamster DPP4 amino acids did not. Using the same approach, the potential of MERS-CoV to utilize the DPP4s of common Middle Eastern livestock was investigated. Modeling of the DPP4 and MERS-CoV RBD interaction predicted the ability of MERS-CoV to bind the DPP4s of camel, goat, cow, and sheep. Expression of the DPP4s of these species on BHK cells supported MERS-CoV replication. This suggests, together with the abundant DPP4 presence in the respiratory tract, that these species might be able to function as a MERS-CoV intermediate reservoir

Energy dependence of exclusive J/ψJ/\psi photoproduction off protons in ultra-peripheral p-Pb collisions at sNN\sqrt{s_{\rm{NN}}} = 5.02 TeV

The ALICE Collaboration has measured the energy dependence of exclusive photoproduction of $J/\psi$ vector mesons off proton targets in ultra-peripheral p-Pb collisions at a centre-of-mass energy per nucleon pair $\sqrt{s_{\rm NN}} = 5.02$ TeV. The e$^+$e$^-$ and $\mu^+\mu^-$ decay channels are used to measure the cross section as a function of the rapidity of the $J/\psi$ in the range $-2.5 < y < 2.7$, corresponding to an energy in the $\gamma$p centre-of-mass in the interval $40 < W_{\gamma\mathrm{p}}<550$ GeV. The measurements, which are consistent with a power law dependence of the exclusive $J/\psi$ photoproduction cross section, are compared to previous results from HERA and the LHC and to several theoretical models. They are found to be compatible with previous measurements.Comment: 25 pages, 3 captioned figures, 3 tables, authors from page 19, published version, figures at http://alice-publications.web.cern.ch/node/455

Measurement of the production of charm jets tagged with D0^{0} mesons in pp collisions at s\sqrt{s}= 7 TeV

The production of charm jets in proton-proton collisions at a center-of-mass energy of $\sqrt{s}=7$ TeV was measured with the ALICE detector at the CERN Large Hadron Collider. The measurement is based on a data sample corresponding to a total integrated luminosity of $6.23$ ${\rm nb}^{-1}$, collected using a minimum-bias trigger. Charm jets are identified by the presence of a D$^0$ meson among their constituents. The D$^0$ mesons are reconstructed from their hadronic decay D$^0\rightarrow$K$^{-}\pi^{+}$. The D$^0$-meson tagged jets are reconstructed using tracks of charged particles (track-based jets) with the anti-$k_{\mathrm{T}}$ algorithm in the jet transverse momentum range $5<p_{\rm{T,jet}}^{\mathrm{ch}}<30$ ${\rm GeV/}c$ and pseudorapidity $|\eta_{\rm jet}|<0.5$. The fraction of charged jets containing a D$^0$-meson increases with $p_{\rm{T,jet}}^{\rm{ch}}$ from $0.042 \pm 0.004\, \mathrm{(stat)} \pm 0.006\, \mathrm{(syst)}$ to $0.080 \pm 0.009\, \rm{(stat)} \pm 0.008\, \rm{(syst)}$. The distribution of D$^0$-meson tagged jets as a function of the jet momentum fraction carried by the D$^0$ meson in the direction of the jet axis ($z_{||}^{\mathrm{ch}}$) is reported for two ranges of jet transverse momenta, $5<p_{\rm{T,jet}}^{\rm{ch}}<15$ ${\rm GeV/}c$ and $15<p_{\rm{T,jet}}^{\rm{ch}}<30$ ${\rm GeV/}c$ in the intervals $0.2<z_{||}^{\rm{ch}}<1.0$ and $0.4<z_{||}^{\rm{ch}}<1.0$, respectively. The data are compared with results from Monte Carlo event generators (PYTHIA 6, PYTHIA 8 and Herwig 7) and with a Next-to-Leading-Order perturbative Quantum Chromodynamics calculation, obtained with the POWHEG method and interfaced with PYTHIA 6 for the generation of the parton shower, fragmentation, hadronisation and underlying event.Comment: 29 pages, 8 captioned figures, 3 tables, authors from page 24, published version, figures at http://alice-publications.web.cern.ch/node/525

High workload and job stress are associated with lower practice performance in general practice: an observational study in 239 general practices in the Netherlands

Contains fulltext : 80493.pdf (publisher's version ) (Open Access)BACKGROUND: The impact of high physician workload and job stress on quality and outcomes of healthcare delivery is not clear. Our study explored whether high workload and job stress were associated with lower performance in general practices in the Netherlands. METHODS: Secondary analysis of data from 239 general practices, collected in practice visits between 2003 to 2006 in the Netherlands using a comprehensive set of measures of practice management. Data were collected by a practice visitor, a trained non-physician observer using patients questionnaires, doctors and staff. For this study we selected five measures of practice performance as outcomes and six measures of GP workload and job stress as predictors. A total of 79 indicators were used out of the 303 available indicators. Random coefficient regression models were applied to examine associations. RESULTS AND DISCUSSION: Workload and job stress are associated with practice performance.Workload: Working more hours as a GP was associated with more positive patient experiences of accessibility and availability (b = 0.16). After list size adjustment, practices with more GP-time per patient scored higher on GP care (b = 0.45). When GPs provided more than 20 hours per week per 1000 patients, patients scored over 80% on the Europep questionnaire for quality of GP care.Job stress: High GP job stress was associated with lower accessibility and availability (b = 0.21) and insufficient practice management (b = 0.25). Higher GP commitment and more satisfaction with the job was associated with more prevention and disease management (b = 0.35). CONCLUSION: Providing more time in the practice, and more time per patient and experiencing less job stress are all associated with perceptions by patients of better care and better practice performance. Workload and job stress should be assessed by using list size adjusted data in order to realise better quality of care. Organisational development using this kind of data feedback could benefit both patients and GP

Infection with Mers-Cov Causes Lethal Pneumonia in the Common Marmoset

The availability of a robust disease model is essential for the development of countermeasures for Middle East respiratory syndrome coronavirus (MERS-CoV). While a rhesus macaque model of MERS-CoV has been established, the lack of uniform, severe disease in this model complicates the analysis of countermeasure studies. Modeling of the interaction between the MERS-CoV spike glycoprotein and its receptor dipeptidyl peptidase 4 predicted comparable interaction energies in common marmosets and humans. The suitability of the marmoset as a MERS-CoV model was tested by inoculation via combined intratracheal, intranasal, oral and ocular routes. Most of the marmosets developed a progressive severe pneumonia leading to euthanasia of some animals. Extensive lesions were evident in the lungs of all animals necropsied at different time points post inoculation. Some animals were also viremic; high viral loads were detected in the lungs of all infected animals, and total RNAseq demonstrated the induction of immune and inflammatory pathways. This is the first description of a severe, partially lethal, disease model of MERS-CoV, and as such will have a major impact on the ability to assess the efficacy of vaccines and treatment strategies as well as allowing more detailed pathogenesis studies

Phagocytosis of Enterovirus-Infected Pancreatic β-Cells Triggers Innate Immune Responses in Human Dendritic Cells

Contains fulltext : 89763.pdf (publisher's version ) (Closed access)OBJECTIVE: Type 1 diabetes is a chronic endocrine disorder in which enteroviruses, such as coxsackie B viruses and echoviruses, are possible environmental factors that can trigger or accelerate disease. The development or acceleration of type 1 diabetes depends on the balance between autoreactive effector T-cells and regulatory T-cells. This balance is particularly influenced by dendritic cells (DCs). The goal of this study was to investigate the interaction between enterovirus-infected human pancreatic islets and human DCs. RESEARCH DESIGN AND METHODS: In vitro phagocytosis of human or porcine primary islets or Min6 mouse insuloma cells by DCs was investigated by flow cytometry and confocal analysis. Subsequent innate DC responses were monitored by quantitative PCR and Western blotting of interferon-stimulated genes (ISGs). RESULTS: In this study, we show that both mock- and coxsackievirus B3 (CVB3)-infected human and porcine pancreatic islets were efficiently phagocytosed by human monocyte-derived DCs. Phagocytosis of CVB3-infected, but not mock-infected, human and porcine islets resulted in induction of ISGs in DCs, including the retinoic acid-inducible gene (RIG)-I-like helicases (RLHs), RIG-I, and melanoma differentiation-associated gene 5 (Mda5). Studies with murine Min6 insuloma cells, which were also efficiently phagocytosed, revealed that increased ISG expression in DCs upon encountering CVB-infected cells resulted in an antiviral state that protected DCs from subsequent enterovirus infection. The observed innate antiviral responses depended on RNA within the phagocytosed cells, required endosomal acidification, and were type I interferon dependent. CONCLUSIONS: Human DCs can phagocytose enterovirus-infected pancreatic cells and subsequently induce innate antiviral responses, such as induction of RLHs. These responses may have important consequences for immune homeostasis in vivo and may play a role in the etiology of type 1 diabetes.1 mei 201

A systematic review of contamination (aerosol, splatter and droplet generation) associated with oral surgery and its relevance to COVID-19

IntroductionThe current COVID-19 pandemic caused by the SARS-CoV-2 virus has impacted the delivery of dental care globally and has led to re-evaluation of infection control standards. However, lack of clarity around what is known and unknown regarding droplet and aerosol generation in dentistry (including oral surgery and extractions), and their relative risk to patients and the dental team, necessitates a review of evidence relating to specific dental procedures. This review is part of a wider body of research exploring the evidence on bioaerosols in dentistry and involves detailed consideration of the risk of contamination in relation to oral surgery.MethodsA comprehensive search of Medline (OVID), Embase (OVID), Cochrane Central Register of Controlled Trials, Scopus, Web of Science, LILACS and ClinicalTrials.Gov was conducted using key terms and MeSH (Medical Subject Headings) words relating to the review questions. Methodological quality including sensitivity was assessed using a schema developed to measure quality aspects of studies using a traffic light system to allow inter- and intra-study overview and comparison. A narrative synthesis was conducted for assessment of the included studies and for the synthesis of results.ResultsEleven studies on oral surgery (including extractions) were included in the review. They explored microbiological (bacterial and fungal) and blood (visible and/or imperceptible) contamination at the person level (patients, operators and assistants) and/or at a wider environmental level, using settle plates, chemiluminescence reagents or air samplers; all within 1 m of the surgical site. Studies were of generally low to medium quality and highlighted an overall risk of contaminated aerosol, droplet and splatter generation during oral surgery procedures, most notably during removal of impacted teeth using rotatory handpieces. Risk of contamination and spread was increased by factors, including proximity to the operatory site, longer duration of treatment, higher procedural complexity, non-use of an extraoral evacuator and areas involving more frequent contact during treatment.ConclusionA risk of contamination (microbiological, visible and imperceptible blood) to patients, dental team members and the clinical environment is present during oral surgery procedures, including routine extractions. However, the extent of contamination has not been explored fully in relation to time and distance. Variability across studies with regards to the analysis methods used and outcome measures makes it difficult to draw robust conclusions. Further studies with improved methodologies, including higher test sensitivity and consideration of viruses, are required to validate these findings