Many transferable quinolone-resistance mechanisms have been already identified in Gram-negative bacteria. The plasmid-encoded 65 amino-acid long ciprofloxacin-modifying enzyme, namely CrpP, was recently identified in Pseudomonas aeruginosa. We analyzed a collection of 100 clonally-unrelated and multidrug-resistant P. aeruginosa clinical isolates among which 46 (46%) were found positive for crpP-like genes, encoding five CrpP variants conferring variable levels of reduced susceptibility to fluoroquinolones. Those crpP-like genes were chromosomally located, as part of PAGI-like pathogenicity genomic islands.

As resistance to artemisinins (current frontline drugs in malaria treatment) emerges in south East Asia, there is an urgent need to identify the genetic determinants and understand the molecular mechanisms underpinning such resistance. Such insights could lead to prospective interventions to contain resistance and prevent the eventual spread to other malaria endemic regions. Artemisinin reduced susceptibility in South East Asia (SEA) has been primarily linked to mutations in P. falciparum Kelch-13, which is currently widely recognised as a molecular marker of artemisinin resistance. However, 2 mutations in a ubiquitin hydrolase, UBP-1, have been previously associated with artemisinin reduced susceptibility in a rodent model of malaria and some cases of UBP-1 mutation variants associating with artemisinin treatment failure have been reported in Africa and SEA. In this study, we have employed CRISPR-Cas9 genome editing and pre-emptive drug pressures to test these artemisinin susceptibility associated mutations in UBP-1 in P. berghei sensitive lines in vivo. Using these approaches, we have shown that the V2721F UBP-1 mutation results in reduced artemisinin susceptibility, while the V2752F mutation results in resistance to chloroquine and moderately impacts tolerance to artemisinins. Genetic reversal of the V2752F mutation restored chloroquine sensitivity in these mutant lines while simultaneous introduction of both mutations could not be achieved and appears to be lethal. Interestingly, these mutations carry a detrimental growth defect, which would possibly explain their lack of expansion in natural infection settings. Our work has provided independent experimental evidence on the role of UBP-1 in modulating parasite responses to artemisinin and chloroquine under in vivo conditions.

Treatment of exacerbations of chronic Pseudomonas aeruginosa infections in patients with cystic fibrosis (CF) is highly challenging due to hypermutability, biofilm formation and an increased risk of resistance emergence. We evaluated the impact of ciprofloxacin and meropenem as monotherapy and in combination in the dynamic in vitro CDC biofilm reactor (CBR). Two hypermutable P. aeruginosa strains, PAOmutS (MIC_{ciprofloxacin} 0.25 mg/L, MIC_meropenem 2 mg/L) and CW44 (MIC_{ciprofloxacin} 0.5 mg/L, MIC_meropenem 4 mg/L), were investigated for 120h. Concentration-time profiles achievable in epithelial lining fluid (ELF) following FDA-approved doses were simulated in the CBR. Treatments were ciprofloxacin 0.4g every 8h as 1h-infusions (80% ELF penetration), meropenem 6 g/day as continuous infusion (CI; 30% and 60% ELF penetration) and their combinations. Counts of total and less-susceptible planktonic and biofilm bacteria and MICs were determined. Antibiotic concentrations were quantified by UHPLC-PDA. For both strains, all monotherapies failed with substantial regrowth and resistance of planktonic (≥8log₁₀ CFU/mL) and biofilm (>8log₁₀ CFU/cm²) bacteria at 120h (MIC_{ciprofloxacin} up to 8 mg/L, MIC_meropenem up to 64 mg/L). Both combination treatments demonstrated synergistic bacterial killing of planktonic and biofilm bacteria of both strains from ~48h onwards and suppressed regrowth to ≤4log₁₀ CFU/mL and ≤6log₁₀ CFU/cm² at 120h. Overall, both combination treatments suppressed amplification of resistance of planktonic bacteria for both strains, and biofilm bacteria for CW44. The combination with meropenem at 60% ELF penetration also suppressed amplification of resistance of biofilm bacteria for PAOmutS. Thus, combination treatment demonstrated synergistic bacterial killing and resistance suppression against difficult-to-treat hypermutable P. aeruginosa strains.

CYP450 enzymes are involved in biotransformation of chloroquine (CQ), but the role of the different metabolism profiles of this drug has not been properly investigated in relation to P. vivax recurrences. To investigate the influence of CYPs genotypes associated with CQ-metabolism on early recurrence rates of P. vivax, a case-control study was carried out. Cases included patients presenting an early recurrence (CQ-recurrent), defined as recurrence during the first 28 days after initial infection, plasma concentrations of CQ plus desethylchloroquine (DCQ, the major CQ metabolite) higher than 100 ng/mL. A control (CQ-responsive) with no parasite recurrence over the follow-up was also included. CQ and DCQ plasma levels were measured on Day 28. CQ CYPs (CYP2C8, CYP3A4 and CYP3A5) genotypes were determined by real-time PCR. An ex vivo study was conducted to verify CQ and DCQ efficacy in P. vivax isolates. The frequency of alleles associated with normal and slow metabolism was similar between the cases and controls for CYP2C8 (OR=1.45, 95% CI=0.51-4.14, p=0.570), CYP3A4 (OR=2.38, 95% CI=0.92-6.19, p=0.105) and CYP3A5 (OR=4.17, 95% CI=0.79-22.04, p=1.038) genes. DCQ levels were higher than CQ, regardless of the genotype. Regarding the DCQ/CQ rate, there was no difference between groups or between those patients who had a normal or mutant genotype. DCQ and CQ showed similar efficacy ex vivo. CYPs genotypes had no influence on early recurrence rates. Similar efficacy of CQ and DCQ ex vivo could explain the absence of therapeutic failure, despite presence of alleles associated with slow metabolism.

Earlier genetic and inhibitor studies have shown that epigenetic regulation of gene expression is critical for malaria parasite survival in multiple life stages and a promising target for new anti-malarials. We therefore evaluated the activity of 350 diverse epigenetic inhibitors against multiple stages of Plasmodium falciparum. We observed ≥90% inhibition at 10 μM for 28% of compounds against asexual blood stages and early gametocytes, of which a third retained ≥90% inhibition at 1 μM.

Background

Optimal concentrations of unbound antimicrobials are essential for maximum microbiological effect. Although hypoalbuminemia and albumin fluid resuscitation are common in critical care, the effects of different albumin concentrations on the unbound concentrations of highly protein-bound antimicrobials are not known. The aim of this study was to compare effects of different albumin states on total and unbound concentrations of ertapenem and ceftriaxone using an ovine model.

Methods

Design

Prospective, three phase intervention observational study.

Subjects

Healthy Merino sheep.

Interventions

Eight sheep were subject to three experimental phases; normoalbuminemia, hypoalbuminemia using plasmapheresis and albumin replacement using a 25% albumin solution. In each phase, ceftriaxone 40 mg/kg and ertapenem 15 mg/kg were given intravenously. Blood samples were collected at pre-defined intervals and analyzed using an ultra-high-performance liquid chromatography tandem mass spectrometry method. Pharmacokinetic parameters such as area under the curve (AUC_0-24), plasma clearance (CL) and apparent volume of distribution in the terminal phase (V_d) were estimated and compared between the phases.

Results

The protein and albumin concentrations were significantly different between phases. Hypoalbuminemia resulted in a significantly lower AUC_0-24 and higher CL of total and unbound concentrations of ceftriaxone compared to the other phases. Whereas albumin replacement led to higher AUC_0-24 and lower CL compared to other phases for both drugs. The V_d for total drug concentrations for both drugs were significantly lower with albumin replacement.

Conclusions

For highly protein-bound drugs such as ceftriaxone and ertapenem, both hypoalbuminemia and albumin replacement may affect unbound drug exposure.

BACKGROUND:

The ability of the decades-old Boston and Philadelphia criteria to accurately identify infants at low risk for serious bacterial infections has not been recently reevaluated.

In an effort to help mitigate the disruptive effects of the deadly COVID-19 virus, an interdisciplinary team of Penn State researchers are developing a novel methodology to analyze its spread and the impacts on policy to create better-prepared and more-resilient health care systems.

For Norwegian international striker Ada Hegerberg, inspiring the next generation of women's players is a personal goal. In an interview which appears in the Women's U17 EURO tournament programme, we hear that the Olympique Lyonnais star wants budding young players to feel her same love of the game.

Teacher-preparation programs need to better prepare teachers, and especially white teachers, to serve students and communities of colors more effectively, the report says.

You may be able to save money and get faster speeds by buying a cable modem instead of renting one from your ISP. Here's what you need to know.

The Model 3 was on Autopilot and managed to rear-end the police car which had stopped to assist a disabled vehicle and had its emergency lights activated.

From the ashes of the failed Fisker Karma sports car, automotive designer Henrik Fisker has designed a futuristic battery-powered luxury SUV that won't break the bank.

We expected the Model Y to ship in the Fall with a 280 mile range, but now it's shipping in March with a 315 mile range.

After months of hard work and preparation, nearly a dozen Penn State Hazleton seniors are now one step closer to graduating after presenting their Capstone Research and Design Thesis projects.

What's CES without a little desktop-PC excess? These dozen products were the ones that mesmerized the PC modder and builder in us.

A new process to harness multiple disease models for outbreak management has been developed by an international team of researchers. The team will immediately implement the process to help inform policy decisions for the COVID-19 outbreak.

Using AI and machine learning capabilities, the system can be further trained to respond like a professional.

"Thank you, parents, for being the best kind of role models. We are because of you," posted Sonam

Review of: Modelling Transitions: Virtues, Vices, Visions of the Future by Moallemi, Enayat A. and de Haan, Fjalar J. (Eds.), reviewed by Cesar Garcia-Diaz

J Jumadi, Nick Malleson, Steve Carver and Duncan Quincey: Managing disasters caused by natural events, especially volcanic crises, requires a range of approaches, including risk modelling and analysis. Risk modelling is commonly conducted at the community/regional scale using GIS. However, people and objects move in response to a crisis, so static approaches cannot capture the dynamics of the risk properly, as they do not accommodate objects’ movements within time and space. The emergence of Agent-Based Modelling makes it possible to model the risk at an individual level as it evolves over space and time. We propose a new approach of Spatio-Temporal Dynamics Model of Risk (STDMR) by integrating multi-criteria evaluation (MCE) within a georeferenced agent-based model, using Mt. Merapi, Indonesia, as a case study. The model makes it possible to simulate the spatio-temporal dynamics of those at risk during a volcanic crisis. Importantly, individual vulnerability is heterogeneous and depends on the characteristics of the individuals concerned. The risk for the individuals is dynamic and changes along with the hazard and their location. The model is able to highlight a small number of high-risk spatio-temporal positions where, due to the behaviour of individuals who are evacuating the volcano and the dynamics of the hazard itself, the overall risk in those times and places is extremely high. These outcomes are extremely relevant for the stakeholders, and the work of coupling an ABM, MCE, and dynamic volcanic hazard is both novel and contextually relevant.

Qing Xu, Sylvie Huet, Eric Perret and Guillaume Deffuant: The drivers of conversion to organic farming, which is still a residual choice in agriculture, are poorly understood. Many scholars argue that farm characteristics can determine this choice but do not exclude the role of social dynamics. To study this issue, we developed an agent-based model in which agents' decisions to shift to organic farming are based on a comparison between satisfaction with the current situation and potential satisfaction with an alternative farming strategy. A farmer agent’s satisfaction is modelled using the Theory of Reasoned Action. This makes it necessary to compare an agent's productions over time with those of other agents to whom the former attributes considerable credibility (“important others”). Moreover, farmers make technical changes that affect their productions by imitating other credible farmers. While we first used this model to examine simple and abstract farm populations, here we also adapted it for use with data from an Agricultural Census concerning the farm characteristics of dairy farming in 27 French “cantons”. Based on domain expertise, data and previous research, we propose certain laws for modelling the impact of conversion on the farm production of milk and the environment. The simulations with “real” populations of farms confirm the important impact of farm characteristics. However, our results also suggest a complex impact of social dynamics that can favour or impede the diffusion of organic farming through dynamic implicit networks of similarity and credibility. We confirm the great importance of demographic changes in farm characteristics.

Alireza Mansouri and Fattaneh Taghiyareh: Human interactions and opinion exchanges lead to social opinion dynamics, which is well described by opinion formation models. In these models, a random parameter is usually considered as the system noise, indicating the individual's inexplicable opinion changes. This noise could be an indicator of any other influential factors, such as public media, affects, and emotions. We study phase transitions, changes from one social phase to another, for various noise levels in a discrete opinion formation model based on the social impact theory with a scale-free random network as its interaction network topology. We also generate another similar model using the concept of social power based on the agents' node degrees in the interaction network as an estimation for their persuasiveness and supportiveness strengths and compare both models from phase transition viewpoint. We show by agent-based simulation and analytical considerations how opinion phases, including majority and non-majority, are formed in terms of the initial population of agents in opinion groups and noise levels. Two factors affect the system phase in equilibrium when the noise level increases: breaking up more segregated groups and dominance of stochastic behavior of the agents on their deterministic behavior. In the high enough noise levels, the system reaches a non-majority phase in equilibrium, regardless of the initial combination of opinion groups. In relatively low noise levels, the original model and the model whose agents' strengths are proportional to their centrality have different behaviors. The presence of a few high-connected influential leaders in the latter model consequences a different behavior in reaching equilibrium phase and different thresholds of noise levels for phase transitions.

Bruno Pietzsch, Sebastian Fiedler, Kai G. Mertens, Markus Richter, Cédric Scherer, Kirana Widyastuti, Marie-Christin Wimmler, Liubov Zakharova and Uta Berger: The recent advancement of agent-based modeling is characterized by higher demands on the parameterization, evaluation and documentation of these computationally expensive models. Accordingly, there is also a growing request for "easy to go" applications just mimicking the input-output behavior of such models. Metamodels are being increasingly used for these tasks. In this paper, we provide an overview of common metamodel types and the purposes of their usage in an agent-based modeling context. To guide modelers in the selection and application of metamodels for their own needs, we further assessed their implementation effort and performance. We performed a literature research in January 2019 using four different databases. Five different terms paraphrasing metamodels (approximation, emulator, meta-model, metamodel and surrogate) were used to capture the whole range of relevant literature in all disciplines. All metamodel applications found were then categorized into specific metamodel types and rated by different junior and senior researches from varying disciplines (including forest sciences, landscape ecology, or economics) regarding the implementation effort and performance. Specifically, we captured the metamodel performance according to (i) the consideration of uncertainties, (ii) the suitability assessment provided by the authors for the particular purpose, and (iii) the number of valuation criteria provided for suitability assessment. We selected 40 distinct metamodel applications from studies published in peer-reviewed journals from 2005 to 2019. These were used for the sensitivity analysis, calibration and upscaling of agent-based models, as well to mimic their prediction for different scenarios. This review provides information about the most applicable metamodel types for each purpose and forms a first guidance for the implementation and validation of metamodels for agent-based models.

Katarzyna Growiec, Jakub Growiec and Bogumił Kamiński: We study the impact of endogenous creation and destruction of social ties in an artificial society on aggregate outcomes such as generalized trust, willingness to cooperate, social utility and economic performance. To this end we put forward a computational multi-agent model where agents of overlapping generations interact in a dynamically evolving social network. In the model, four distinct dimensions of individuals’ social capital: degree, centrality, heterophilous and homophilous interactions, determine their generalized trust and willingness to cooperate, altogether helping them achieve certain levels of social utility (i.e., utility from social contacts) and economic performance. We find that the stationary state of the simulated social network exhibits realistic small-world topology. We also observe that societies whose social networks are relatively frequently reconfigured, display relatively higher generalized trust, willingness to cooperate, and economic performance – at the cost of lower social utility. Similar outcomes are found for societies where social tie dissolution is relatively weakly linked to family closeness.

Szymon Talaga and Andrzej Nowak: Real-world social networks often exhibit high levels of clustering, positive degree assortativity, short average path lengths (small-world property) and right-skewed but rarely power law degree distributions. On the other hand homophily, defined as the propensity of similar agents to connect to each other, is one of the most fundamental social processes observed in many human and animal societies. In this paper we examine the extent to which homophily is sufficient to produce the typical structural properties of social networks. To do so, we conduct a simulation study based on the Social Distance Attachment (SDA) model, a particular kind of Random Geometric Graph (RGG), in which nodes are embedded in a social space and connection probabilities depend functionally on distances between nodes. We derive the form of the model from first principles based on existing analytical results and argue that the mathematical construction of RGGs corresponds directly to the homophily principle, so they provide a good model for it. We find that homophily, especially when combined with a random edge rewiring, is sufficient to reproduce many of the characteristic features of social networks. Additionally, we devise a hybrid model combining SDA with the configuration model that allows generating homophilic networks with arbitrary degree sequences and we use it to study interactions of homophily with processes imposing constraints on degree distributions. We show that the effects of homophily on clustering are robust with respect to distribution constraints, while degree assortativity can be highly dependent on the particular kind of enforced degree sequence.

Myong-Hun Chang and Joseph Harrington: The dynamics of social stigma are explored in the context of diffusion models. Our focus is on exploring the dynamic process through which the behavior of individuals and the interpersonal relationships among them influence the macro-social attitude towards the stigma. We find that a norm of tolerance is best promoted when the population comprises both those whose conduct is driven by compassion for the stigmatized and those whose focus is on conforming with others in their social networks. A second finding is that less insular social networks encourage de-stigmatization when most people are compassionate, but it is instead more insularity that promotes tolerance when society is dominated by conformity.

Volker Grimm, Steven F. Railsback, Christian E. Vincenot, Uta Berger, Cara Gallagher, Donald L. DeAngelis, Bruce Edmonds, Jiaqi Ge, Jarl Giske, Jürgen Groeneveld, Alice S.A. Johnston, Alexander Milles, Jacob Nabe-Nielsen, J. Gareth Polhill, Viktoriia Radchuk, Marie-Sophie Rohwäder, Richard A. Stillman, Jan C. Thiele and Daniel Ayllón: The Overview, Design concepts and Details (ODD) protocol for describing Individual- and Agent-Based Models (ABMs) is now widely accepted and used to document such models in journal articles. As a standardized document for providing a consistent, logical and readable account of the structure and dynamics of ABMs, some research groups also find it useful as a workflow for model design. Even so, there are still limitations to ODD that obstruct its more widespread adoption. Such limitations are discussed and addressed in this paper: the limited availability of guidance on how to use ODD; the length of ODD documents; limitations of ODD for highly complex models; lack of sufficient details of many ODDs to enable reimplementation without access to the model code; and the lack of provision for sections in the document structure covering model design rationale, the model’s underlying narrative, and the means by which the model’s fitness for purpose is evaluated. We document the steps we have taken to provide better guidance on: structuring complex ODDs and an ODD summary for inclusion in a journal article (with full details in supplementary material; Table 1); using ODD to point readers to relevant sections of the model code; update the document structure to include sections on model rationale and evaluation. We also further advocate the need for standard descriptions of simulation experiments and argue that ODD can in principle be used for any type of simulation model. Thereby ODD would provide a lingua franca for simulation modelling.

Flaminio Squazzoni, J. Gareth Polhill, Bruce Edmonds, Petra Ahrweiler, Patrycja Antosz, Geeske Scholz, Émile Chappin, Melania Borit, Harko Verhagen, Francesca Giardini and Nigel Gilbert: The COVID-19 pandemic is causing a dramatic loss of lives worldwide, challenging the sustainability of our health care systems, threatening economic meltdown, and putting pressure on the mental health of individuals (due to social distancing and lock-down measures). The pandemic is also posing severe challenges to the scientific community, with scholars under pressure to respond to policymakers’ demands for advice despite the absence of adequate, trusted data. Understanding the pandemic requires fine-grained data representing specific local conditions and the social reactions of individuals. While experts have built simulation models to estimate disease trajectories that may be enough to guide decision-makers to formulate policy measures to limit the epidemic, they do not cover the full behavioural and social complexity of societies under pandemic crisis. Modelling that has such a large potential impact upon people’s lives is a great responsibility. This paper calls on the scientific community to improve the transparency, access, and rigour of their models. It also calls on stakeholders to improve the rapidity with which data from trusted sources are released to the community (in a fully responsible manner). Responding to the pandemic is a stress test of our collaborative capacity and the social/economic value of research.

 Seeks to amend noti.No.146/94-Customs dated 13.07.94 so as to modify conditions for shooting equipment

Weekday – This route is operating on a Saturday schedule.

Weekend – DART is operating normal weekend service.

If you are feeling sick, please do not take public transit or visit public facilities. For more information on the state's response to the Coronavirus, visit de.gov/coronavirus.

Thank you.

Route 18 is operating on limited service, the trips are highlighted in yellow on the PDF schedule.

If you are feeling sick, please do not take public transit or visit public facilities. For more information on the state's response to the Coronavirus, visit de.gov/coronavirus.

Thank you.

Weekday – Route 15 is operating on a Saturday schedule and has added additional weekday trips to its schedule that are highlighted in yellow on the PDF schedule.

Weekend – DART is operating normal weekend service.

If you are feeling sick, please do not take public transit or visit public facilities. For more information on the state's response to the Coronavirus, visit de.gov/coronavirus.

Thank you.

Weekday – Route 301 is operating on a Saturday schedule and has added additional weekday trips to its schedule that are highlighted in yellow on the PDF schedule.

Saturday – DART is operating normal weekend service.

If you are feeling sick, please do not take public transit or visit public facilities. For more information on the state's response to the Coronavirus, visit de.gov/coronavirus.

Thank you.

Weekday – This route is operating on a Saturday schedule.

Saturday – DART is operating normal Saturday service.

If you are feeling sick, please do not take public transit or visit public facilities. For more information on the state's response to the Coronavirus, visit de.gov/coronavirus.

Thank you.

Weekday – This route is operating on a Saturday schedule.

Saturday – DART is operating normal Saturday service.

If you are feeling sick, please do not take public transit or visit public facilities. For more information on the state's response to the Coronavirus, visit de.gov/coronavirus.

Thank you.

India currently has solar modules manufacturing capacity of 7-8 gigawatts (GW). This includes the units of players like Adani Solar, Tata Solar, Waaree Energies and Vikram Solar.

In view of the mounting attacks amid the Coronavirus outbreak, the IMA had been demanding that the government formulate a law to protect health workers.

Given the Indian economy could well contract in 2020-21,following the disruption to the pandemic, even bigger companies might enourage some employees to work from home. For small businesses there might be no other option.

Uttarakhand Chief Minister Trivendra Singh Rawat said businesses should start operations in a phased manner, after taking precautionary measures.

The concern is genuine as new hotspots are emerging in districts like Idukki and Kottayam that were earlier in the green zone and considered safe.

Using R programming, marketers can create a marketing mix model to determine how sustainable their audience channels are, and make better ad spend decisions. Here's how

Anglers encouraged to practice responsible social distancing. Trout streams closed March 21 until opening.

In consultation with the Delaware Department of Insurance, Governor John Carney today issued a sixth modification to the state of emergency that requires that insurers cease cancellations or nonrenewals of insurance policies due to nonpayment throughout the duration of the declared Delaware State of Emergency for those residents and business owners who are experiencing a […]

Modification provides additional protections for Delaware renters WILMINGTON, Del. – Governor John Carney on Thursday issued the fourteenth modification to his State of Emergency declaration, providing additional protections for Delaware renters during the COVID-19 pandemic, and extending the application deadline for Delaware’s Senior School Property Tax Credit Program until June 1.  Click here to read the full text […]

La modificación prevé protecciones adicionales para los arrendatarios de Delaware   WILMINGTON, Del. – El gobernador John Carney emitió el jueves la decimocuarta modificación a su declaración de Estado de Emergencia, la cual prevé protecciones adicionales para los arrendatarios de Delaware durante la pandemia de COVID-19, y extiende hasta el 1.° de junio la fecha […]

Modifikasyon an bay plis pwoteksyon pou lokatènan Delaware   WILMINGTON, Del. – Gouvènè John Carney te pibliye nan Jedi a katòzyèm modifikasyon sou deklarasyon ijans li a, bay plispwoteksyon pou lokatè nan Delaware pandan pandemi COVID-19 la, epi pwolonje dat limit aplikasyon pou pwogram kredi sou TaksPwopriyete nan Lekòl Segondè ki nan Delaware jiska 1ye jen.  Klike […]

Only the Countryman now is available with a diesel engine in India while all other models come with the familiar 2.0-litre petrol motor.