The use of segmented regression in analysing interrupted time series studies : an example in pre-hospital ambulance care

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The POINT-AGAPE Survey: Comparing Automated Searches of Microlensing Events toward M31

Searching for microlensing in M31 using automated superpixel surveys raises a number of difficulties which are not present in more conventional techniques. Here we focus on the problem that the list of microlensing candidates is sensitive to the selection criteria or "cuts" imposed and some subjectivity is involved in this. Weakening the cuts will generate a longer list of microlensing candidates but with a greater fraction of spurious ones; strengthening the cuts will produce a shorter list but may exclude some genuine events. We illustrate this by comparing three analyses of the same data-set obtained from a 3-year observing run on the INT in La Palma. The results of two of these analyses have been already reported: Belokurov et al. (2005) obtained between 3 and 22 candidates, depending on the strength of their cuts, while Calchi Novati et al. (2005) obtained 6 candidates. The third analysis is presented here for the first time and reports 10 microlensing candidates, 7 of which are new. Only two of the candidates are common to all three analyses. In order to understand why these analyses produce different candidate lists, a comparison is made of the cuts used by the three groups...Comment: 28 pages, 24 figures, 9 table

The POINT-AGAPE survey II: An Unrestricted Search for Microlensing Events towards M31

An automated search is carried out for microlensing events using a catalogue of 44554 variable superpixel lightcurves derived from our three-year monitoring program of M31. Each step of our candidate selection is objective and reproducible by a computer. Our search is unrestricted, in the sense that it has no explicit timescale cut. So, it must overcome the awkward problem of distinguishing long-timescale microlensing events from long-period stellar variables. The basis of the selection algorithm is the fitting of the superpixel lightcurves to two different theoretical models, using variable star and blended microlensing templates. Only if microlensing is preferred is an event retained as a possible candidate. Further cuts are made with regard to (i) sampling, (ii) goodness of fit of the peak to a Paczynski curve, (iii) consistency of the microlensing hypothesis with the absence of a resolved source, (iv) achromaticity, (v) position in the colour-magnitude diagram and (vi) signal-to-noise ratio. Our results are reported in terms of first-level candidates, which are the most trustworthy, and second-level candidates, which are possible microlensing but have lower signal-to-noise and are more questionable. The pipeline leaves just 3 first-level candidates, all of which have very short full-width half-maximum timescale (<5 days) and 3 second-level candidates, which have timescales of 31, 36 and 51 days respectively. We also show 16 third-level lightcurves, as an illustration of the events that just fail the threshold for designation as microlensing candidates. They are almost certainly mainly variable stars. Two of the 3 first-level candidates correspond to known events (PA 00-S3 and PA 00-S4) already reported by the POINT-AGAPE project. The remaining first-level candidate is new.Comment: 22 pages, 18 figures, MNRAS, to appea

Search for exoplanets in M31 with pixel-lensing and the PA-99-N2 event revisited

Several exoplanets have been detected towards the Galactic bulge with the microlensing technique. We show that exoplanets in M31 may also be detected with the pixel-lensing method, if telescopes making high cadence observations of an ongoing microlensing event are used. Using a Monte Carlo approach we find that the mean mass for detectable planetary systems is about $2 M_{\rm {J}}$. However, even small mass exoplanets ($M_{\rm P} < 20 M_{\oplus}$) can cause significant deviations, which are observable with large telescopes. We reanalysed the POINT-AGAPE microlensing event PA-99-N2. First, we test the robustness of the binary lens conclusion for this light curve. Second, we show that for such long duration and bright microlensing events, the efficiency for finding planetary-like deviations is strongly enhanced with respect to that evaluated for all planetary detectable events.Comment: 14 pages, 8 figures. Paper presented at the "II Italian-Pakistani Workshop on Relativistic Astrophysics, Pescara, July 8-10, 2009. To be published in a special issue of General Relativity and Gravitation (eds. F. De Paolis, G.F.R. Ellis, A. Qadir and R. Ruffini

The Anomaly in the Candidate Microlensing Event PA-99-N2

The lightcurve of PA-99-N2, one of the recently announced microlensing candidates towards M31, shows small deviations from the standard Paczynski form. We explore a number of possible explanations, including correlations with the seeing, the parallax effect and a binary lens. We find that the observations are consistent with an unresolved RGB or AGB star in M31 being microlensed by a binary lens. We find that the best fit binary lens mass ratio is about one hundredth, which is one of most extreme values found for a binary lens so far. If both the source and lens lie in the M31 disk, then the standard M31 model predicts the probable mass range of the system to be 0.02-3.6 solar masses (95 % confidence limit). In this scenario, the mass of the secondary component is therefore likely to be below the hydrogen-burning limit. On the other hand, if a compact halo object in M31 is lensing a disk or spheroid source, then the total lens mass is likely to lie between 0.09-32 solar masses, which is consistent with the primary being a stellar remnant and the secondary a low mass star or brown dwarf. The optical depth (or alternatively the differential rate) along the line of sight toward the event indicates that a halo lens is more likely than a stellar lens provided that dark compact objects comprise no less than 15 per cent (or 5 per cent) of haloes.Comment: Latex, 23 pages, 9 figures, in press at The Astrophysical Journa

X-ray monitoring of classical novae in the central region of M 31. II. Autumn and winter 2007/2008 and 2008/2009

[Abridged] Classical novae (CNe) represent the major class of supersoft X-ray sources (SSSs) in the central region of our neighbouring galaxy M 31. We performed a dedicated monitoring of the M 31 central region with XMM-Newton and Chandra between Nov 2007 and Feb 2008 and between Nov 2008 and Feb 2009 respectively, in order to find SSS counterparts of CNe, determine the duration of their SSS phase and derive physical outburst parameters. We systematically searched our data for X-ray counterparts of CNe and determined their X-ray light curves and spectral properties. We detected in total 17 X-ray counterparts of CNe in M 31, only four of which were known previously. These latter sources are still active 12.5, 11.0, 7.4 and 4.8 years after the optical outburst. From the 17 X-ray counterparts 13 were classified as SSSs. Four novae displayed short SSS phases (< 100 d). Based on these results and previous studies we compiled a catalogue of all novae with SSS counterparts in M 31 known so far. We used this catalogue to derive correlations between the following X-ray and optical nova parameters: turn-on time, turn-off time, effective temperature (X-ray), t2 decay time and expansion velocity of the ejected envelope (optical). Furthermore, we found a first hint for the existence of a difference between SSS parameters of novae associated with the stellar populations of the M 31 bulge and disk. Additionally, we conducted a Monte Carlo Markov Chain simulation on the intrinsic fraction of novae with SSS phase. This simulation showed that the relatively high fraction of novae without detected SSS emission might be explained by the inevitably incomplete coverage with X-ray observations in combination with a large fraction of novae with short SSS states, as expected from the WD mass distribution. In order to verify our results with an increased sample further monitoring observations are needed.Comment: 31 pages, 23 figures, 10 tables; submitted to A&

Attenuation of porcine reproductive and respiratory syndrome virus by molecular breeding of virus envelope genes from genetically divergent strains

Molecular breeding via DNA shuffling can direct the evolution of viruses with desired traits. By using a positive-strand RNA virus, porcine reproductive and respiratory syndrome virus (PRRSV), as a model, rapid attenuation of the virus was achieved in this study by DNA shuffling of the viral envelope genes from multiple strains. The GP5 envelope genes of 7 genetically divergent PRRSV strains and the GP5-M genes of 6 different PRRSV strains were molecularly bred by DNA shuffling and iteration of the process, and the shuffled genes were cloned into the backbone of a DNA-launched PRRSV infectious clone. Two representative chimeric viruses, DS722 with shuffled GP5 genes and DS5M3 with shuffled GP5-M genes, were rescued and shown to replicate at a lower level and to form smaller plaques in vitro than their parental virus. An in vivo pathogenicity study revealed that pigs infected with the two chimeric viruses had significant reductions in viral-RNA loads in sera and lungs and in gross and microscopic lung lesions, indicating attenuation of the chimeric viruses. Furthermore, pigs vaccinated with the chimeric virus DS722, but not pigs vaccinated with DS5M3, still acquired protection against PRRSV challenge at a level similar to that of the parental virus. Therefore, this study reveals a unique approach through DNA shuffling of viral envelope genes to attenuate a positive-strand RNA virus. The results have important implications for future vaccine development and will generate broad general interest in the scientific community in rapidly attenuating other important human and veterinary viruses

Combined search for the quarks of a sequential fourth generation

Results are presented from a search for a fourth generation of quarks produced singly or in pairs in a data set corresponding to an integrated luminosity of 5 inverse femtobarns recorded by the CMS experiment at the LHC in 2011. A novel strategy has been developed for a combined search for quarks of the up and down type in decay channels with at least one isolated muon or electron. Limits on the mass of the fourth-generation quarks and the relevant Cabibbo-Kobayashi-Maskawa matrix elements are derived in the context of a simple extension of the standard model with a sequential fourth generation of fermions. The existence of mass-degenerate fourth-generation quarks with masses below 685 GeV is excluded at 95% confidence level for minimal off-diagonal mixing between the third- and the fourth-generation quarks. With a mass difference of 25 GeV between the quark masses, the obtained limit on the masses of the fourth-generation quarks shifts by about +/- 20 GeV. These results significantly reduce the allowed parameter space for a fourth generation of fermions.Comment: Replaced with published version. Added journal reference and DO

Insect pathogens as biological control agents: back to the future

The development and use of entomopathogens as classical, conservation and augmentative biological control agents have included a number of successes and some setbacks in the past 15 years. In this forum paper we present current information on development, use and future directions of insect-specific viruses, bacteria, fungi and nematodes as components of integrated pest management strategies for control of arthropod pests of crops, forests, urban habitats, and insects of medical and veterinary importance. Insect pathogenic viruses are a fruitful source of MCAs, particularly for the control of lepidopteran pests. Most research is focused on the baculoviruses, important pathogens of some globally important pests for which control has become difficult due to either pesticide resistance or pressure to reduce pesticide residues. Baculoviruses are accepted as safe, readily mass produced, highly pathogenic and easily formulated and applied control agents. New baculovirus products are appearing in many countries and gaining an increased market share. However, the absence of a practical in vitro mass production system, generally higher production costs, limited post application persistence, slow rate of kill and high host specificity currently contribute to restricted use in pest control. Overcoming these limitations are key research areas for which progress could open up use of insect viruses to much larger markets. A small number of entomopathogenic bacteria have been commercially developed for control of insect pests. These include several Bacillus thuringiensis sub-species, Lysinibacillus (Bacillus) sphaericus, Paenibacillus spp. and Serratia entomophila. B. thuringiensis sub-species kurstaki is the most widely used for control of pest insects of crops and forests, and B. thuringiensis sub-species israelensis and L. sphaericus are the primary pathogens used for medically important pests including dipteran vectors,. These pathogens combine the advantages of chemical pesticides and microbial control agents (MCAs): they are fast acting, easy to produce at a relatively low cost, easy to formulate, have a long shelf life and allow delivery using conventional application equipment and systemics (i.e. in transgenic plants). Unlike broad spectrum chemical pesticides, B. thuringiensis toxins are selective and negative environmental impact is very limited. Of the several commercially produced MCAs, B. thuringiensis (Bt) has more than 50% of market share. Extensive research, particularly on the molecular mode of action of Bt toxins, has been conducted over the past two decades. The Bt genes used in insect-resistant transgenic crops belong to the Cry and vegetative insecticidal protein families of toxins. Bt has been highly efficacious in pest management of corn and cotton, drastically reducing the amount of broad spectrum chemical insecticides used while being safe for consumers and non-target organisms. Despite successes, the adoption of Bt crops has not been without controversy. Although there is a lack of scientific evidence regarding their detrimental effects, this controversy has created the widespread perception in some quarters that Bt crops are dangerous for the environment. In addition to discovery of more efficacious isolates and toxins, an increase in the use of Bt products and transgenes will rely on innovations in formulation, better delivery systems and ultimately, wider public acceptance of transgenic plants expressing insect-specific Bt toxins. Fungi are ubiquitous natural entomopathogens that often cause epizootics in host insects and possess many desirable traits that favor their development as MCAs. Presently, commercialized microbial pesticides based on entomopathogenic fungi largely occupy niche markets. A variety of molecular tools and technologies have recently allowed reclassification of numerous species based on phylogeny, as well as matching anamorphs (asexual forms) and teleomorphs (sexual forms) of several entomopathogenic taxa in the Phylum Ascomycota. Although these fungi have been traditionally regarded exclusively as pathogens of arthropods, recent studies have demonstrated that they occupy a great diversity of ecological niches. Entomopathogenic fungi are now known to be plant endophytes, plant disease antagonists, rhizosphere colonizers, and plant growth promoters. These newly understood attributes provide possibilities to use fungi in multiple roles. In addition to arthropod pest control, some fungal species could simultaneously suppress plant pathogens and plant parasitic nematodes as well as promote plant growth. A greater understanding of fungal ecology is needed to define their roles in nature and evaluate their limitations in biological control. More efficient mass production, formulation and delivery systems must be devised to supply an ever increasing market. More testing under field conditions is required to identify effects of biotic and abiotic factors on efficacy and persistence. Lastly, greater attention must be paid to their use within integrated pest management programs; in particular, strategies that incorporate fungi in combination with arthropod predators and parasitoids need to be defined to ensure compatibility and maximize efficacy. Entomopathogenic nematodes (EPNs) in the genera Steinernema and Heterorhabditis are potent MCAs. Substantial progress in research and application of EPNs has been made in the past decade. The number of target pests shown to be susceptible to EPNs has continued to increase. Advancements in this regard primarily have been made in soil habitats where EPNs are shielded from environmental extremes, but progress has also been made in use of nematodes in above-ground habitats owing to the development of improved protective formulations. Progress has also resulted from advancements in nematode production technology using both in vivo and in vitro systems; novel application methods such as distribution of infected host cadavers; and nematode strain improvement via enhancement and stabilization of beneficial traits. Innovative research has also yielded insights into the fundamentals of EPN biology including major advances in genomics, nematode-bacterial symbiont interactions, ecological relationships, and foraging behavior. Additional research is needed to leverage these basic findings toward direct improvements in microbial control

Value of hospital antimicrobial stewardship programs [ASPs]:a systematic review

Abstract Background Hospital antimicrobial stewardship programs (ASPs) aim to promote judicious use of antimicrobials to combat antimicrobial resistance. For ASPs to be developed, adopted, and implemented, an economic value assessment is essential. Few studies demonstrate the cost-effectiveness of ASPs. This systematic review aimed to evaluate the economic and clinical impact of ASPs. Methods An update to the Dik et al. systematic review (2000–2014) was conducted on EMBASE and Medline using PRISMA guidelines. The updated search was limited to primary research studies in English (30 September 2014–31 December 2017) that evaluated patient and/or economic outcomes after implementation of hospital ASPs including length of stay (LOS), antimicrobial use, and total (including operational and implementation) costs. Results One hundred forty-six studies meeting inclusion criteria were included. The majority of these studies were conducted within the last 5 years in North America (49%), Europe (25%), and Asia (14%), with few studies conducted in Africa (3%), South America (3%), and Australia (3%). Most studies were conducted in hospitals with 500–1000 beds and evaluated LOS and change in antibiotic expenditure, the majority of which showed a decrease in LOS (85%) and antibiotic expenditure (92%). The mean cost-savings varied by hospital size and region after implementation of ASPs. Average cost savings in US studies were $732 per patient (range:$2.50 to $2640), with similar trends exhibited in European studies. The key driver of cost savings was from reduction in LOS. Savings were higher among hospitals with comprehensive ASPs which included therapy review and antibiotic restrictions. Conclusions Our data indicates that hospital ASPs have significant value with beneficial clinical and economic impacts. More robust published data is required in terms of implementation, LOS, and overall costs so that decision-makers can make a stronger case for investing in ASPs, considering competing priorities. Such data on ASPs in lower- and middle-income countries is limited and requires urgent attention