Optimized testing and lockdown strategies for epidemic control, case COVID-19

The ongoing COVID-19 epidemic poses a difficult decision making situation: Too light or late measures to control the epidemic might lead to high casualties and human suffering, too heavy measures might cause economic damage, which in turn can have far-reaching effects on human health and quality of life. Optimization is a widely used technique for dealing with complex decision making situations. Combined with epidemic and economic modeling, it can help decision makers in choosing efficient strategies for epidemic control. In this work, we propose a modeling approach to support decision making with regards to timing and strength of lockdown and testing measures. The approach combines optimization with a compartmental epidemic model to account for both spread of the disease and the role of testing and interventions, including contact tracing, in mitigating it. We provide a framework for optimizing epidemic control strategies and highlight main implications for the cases similar to COVID-19

Voriconazole and fluconazole increase the exposure to oral diazepam

Conclusion Both voriconazole and fluconazole considerably increase the exposure to diazepam. Recurrent administration of diazepam increases the risk of clinically significant interactions during voriconazole or fluconazole treatment, because the elimination of diazepam is impaired significantly

Supporting strategy selection in multiobjective decision problems under uncertainty and hidden requirements

Decision-makers are often faced with multi-faceted problems that require making trade-offs between multiple, conflicting objectives under various uncertainties. The task is even more difficult when considering dynamic, non-linear processes and when the decisions themselves are complex, for instance in the case of selecting trajectories for multiple decision variables. These types of problems are often solved using multiobjective optimization (MOO). A typical problem in MOO is that the number of Pareto optimal solutions can be very large, whereby the selection process of a single preferred solution is cumbersome. Moreover, preference between model-based solutions may not be determined only by their objective function values, but also in terms of how robust and implementable these solutions are. In this paper, we develop a methodological framework to support the identification of a small but diverse set of robust Pareto optimal solutions. In particular, we eliminate non-robust solutions from the Pareto front and cluster the remaining solutions based on their similarity in the decision variable space. This enables a manageable visual inspection of the remaining solutions to compare them in terms of practical implementability. We illustrate the framework and its benefits by means of an epidemic control problem that minimizes deaths and economic impacts, and a screening program for colorectal cancer that minimizes cancer prevalence and costs. These examples highlight the general applicability of the framework for disparate types of decision problems and process models

Viral and Bacterial Pathogens in Bovine Respiratory Disease in Finland

Pathogens causing bovine respiratory tract disease in Finland were investigated. Eighteen cattle herds with bovine respiratory disease were included. Five diseased calves from each farm were chosen for closer examination and tracheobronchial lavage. Blood samples were taken from the calves at the time of the investigation and from 86 calves 3–4 weeks later. In addition, 6–10 blood samples from animals of different ages were collected from each herd, resulting in 169 samples. Serum samples were tested for antibodies to bovine parainfluenza virus-3 (PIV-3), bovine respiratory syncytial virus (BRSV), bovine coronavirus (BCV), bovine adenovirus-3 (BAV-3) and bovine adenovirus-7 (BAV-7). About one third of the samples were also tested for antibodies to bovine virus diarrhoea virus (BVDV) with negative results. Bacteria were cultured from lavage fluid and in vitro susceptibility to selected antimicrobials was tested. According to serological findings, PIV-3, BAV-7, BAV-3, BCV and BRSV are common pathogens in Finnish cattle with respiratory problems. A titre rise especially for BAV-7 and BAV-3, the dual growth of Mycoplasma dispar and Pasteurella multocida, were typical findings in diseased calves. Pasteurella sp. strains showed no resistance to tested antimicrobials. Mycoplasma bovis and Mannheimia haemolytica were not found

A Mechanistic, Model-Based Approach to Safety Assessment in Clinical Development

Peer reviewe

SH3 Domain-Mediated Recruitment of Host Cell Amphiphysins by Alphavirus nsP3 Promotes Viral RNA Replication

Among the four non-structural proteins of alphaviruses the function of nsP3 is the least well understood. NsP3 is a component of the viral replication complex, and composed of a conserved aminoterminal macro domain implicated in viral RNA synthesis, and a poorly conserved carboxyterminal region. Despite the lack of overall homology we noted a carboxyterminal proline-rich sequence motif shared by many alphaviral nsP3 proteins, and found it to serve as a preferred target site for the Src-homology 3 (SH3) domains of amphiphysin-1 and -2. Nsp3 proteins of Semliki Forest (SFV), Sindbis (SINV), and Chikungunya viruses all showed avid and SH3-dependent binding to amphiphysins. Upon alphavirus infection the intracellular distribution of amphiphysin was dramatically altered and colocalized with nsP3. Mutations in nsP3 disrupting the amphiphysin SH3 binding motif as well as RNAi-mediated silencing of amphiphysin-2 expression resulted in impaired viral RNA replication in HeLa cells infected with SINV or SFV. Infection of Balb/c mice with SFV carrying an SH3 binding-defective nsP3 was associated with significantly decreased mortality. These data establish SH3 domain-mediated binding of nsP3 with amphiphysin as an important host cell interaction promoting alphavirus replication

Treatment of developmental dyslexia: A review

Remarkably few research articles on the treatment of developmental dyslexia were published during the last 25 years. Some treatment research arose from the temporal processing theory, some from the phonological deficit hypothesis and some more from the balance model of learning to read and dyslexia. Within the framework of that model, this article reviews the aetiology of dyslexia sub-types, the neuropsychological rationale for treatment, the treatment techniques and the outcomes of treatment research. The possible mechanisms underlying the effects of treatment are discussed. © 2005 Informa UK Ltd All rights reserved

SNAP-tagged Chikungunya Virus Replicons Improve Visualisation of Non-Structural Protein 3 by Fluorescence Microscopy

Chikungunya virus (CHIKV), a mosquito-borne alphavirus, causes febrile disease, muscle and joint pain, which can become chronic in some individuals. The non-structural protein 3 (nsP3) plays essential roles during infection, but a complete understanding of its function is lacking. Here we used a microscopy-based approach to image CHIKV nsP3 inside human cells. The SNAP system consists of a self-labelling enzyme tag, which catalyses the covalent linking of exogenously supplemented synthetic ligands. Genetic insertion of this tag resulted in viable replicons and specific labelling while preserving the effect of nsP3 on stress granule responses and co-localisation with GTPase Activating Protein (SH3 domain) Binding Proteins (G3BPs). With sub-diffraction, three-dimensional, optical imaging, we visualised nsP3-positive structures with variable density and morphology, including high-density rod-like structures, large spherical granules, and small, low-density structures. Next, we confirmed the utility of the SNAP tag for studying protein turnover by pulse-chase labelling. We also revealed an association of nsP3 with cellular lipid droplets and examined the spatial relationships between nsP3 and the non-structural protein 1 (nsP1). Together, our study provides a sensitive, specific, and versatile system for fundamental research into the individual functions of a viral non-structural protein during infection with a medically important arthropod-borne virus (arbovirus)

Two Legionnaires' disease cases associated with industrial waste water treatment plants: a case report

<p>Abstract</p> <p>Background</p> <p>Finnish and Swedish waste water systems used by the forest industry were found to be exceptionally heavily contaminated with legionellae in 2005.</p> <p>Case presentation</p> <p>We report two cases of severe pneumonia in employees working at two separate mills in Finland in 2006. <it>Legionella </it>serological and urinary antigen tests were used to diagnose Legionnaires' disease in the symptomatic employees, who had worked at, or close to, waste water treatment plants. Since the findings indicated a <it>Legionella </it>infection, the waste water and home water systems were studied in more detail. The antibody response and <it>Legionella </it>urinary antigen finding of Case A indicated that the infection had been caused by <it>Legionella pneumophila </it>serogroup 1. Case A had been exposed to legionellae while installing a pump into a post-clarification basin at the waste water treatment plant of mill A. Both the water and sludge in the basin contained high concentrations of <it>Legionella pneumophila </it>serogroup 1, in addition to serogroups 3 and 13. Case B was working 200 meters downwind from a waste water treatment plant, which had an active sludge basin and cooling towers. The antibody response indicated that his disease was due to <it>Legionella pneumophila </it>serogroup 2. The cooling tower was the only site at the waste water treatment plant yielding that serogroup, though water in the active sludge basin yielded abundant growth of <it>Legionella pneumophila </it>serogroup 5 and <it>Legionella rubrilucens</it>. Both workers recovered from the disease.</p> <p>Conclusion</p> <p>These are the first reported cases of Legionnaires' disease in Finland associated with industrial waste water systems.</p