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  • Authors: G, Remington; J, Lee; O, Agid; H, Takeuchi; +5 Authors

    Clozapine was first introduced as an antipsychotic in the 1970's but a cluster of deaths, later linked to the drug's risk of agranulocytosis, led to its withdrawal in most countries. However, work in the 1980's established its unique efficacy in treatment resistant schizophrenia (TRS), which constitutes as many as 30% of those with the illness. Clozapine was reintroduced with this indication shortly thereafter, but because of this risk its use requires routine hematologic monitoring.An update is provided regarding clozapine's risk of neutropenia, agranulocytosis, and associated mortality. In addition, updates are provided on other side effects, specifically myocarditis and bowel obstruction, as evidence suggests these are more common than agranulocytosis and associated with higher mortality rates.Clozapine remains the only treatment indicated in TRS, but it is dramatically underutilized. Clearly there are serious side effects associated with its use, and while the focus has historically been on hematologic concerns, we highlight other side effects that also demand systematic monitoring. Because it is the only effective treatment option we have for TRS, though, efforts must be implemented that ensure its use in this population while maximizing safety.

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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Marisa C. Hamilton; James D. Fife; Ersin Akinci; Tian Yu; +13 Authors

    SummaryGenetic variation contributes greatly to LDL cholesterol (LDL-C) levels and coronary artery disease risk. By combining analysis of rare coding variants from the UK Biobank and genome-scale CRISPR-Cas9 knockout and activation screening, we have substantially improved the identification of genes whose disruption alters serum LDL-C levels. We identify 21 genes in which rare coding variants significantly alter LDL-C levels at least partially through altered LDL-C uptake. We use co-essentiality-based gene module analysis to show that dysfunction of the RAB10 vesicle transport pathway leads to hypercholesterolemia in humans and mice by impairing surface LDL receptor levels. Further, we demonstrate that loss of function ofOTX2leads to robust reduction in serum LDL-C levels in mice and humans by increasing cellular LDL-C uptake. Altogether, we present an integrated approach that improves our understanding of genetic regulators of LDL-C levels and provides a roadmap for further efforts to dissect complex human disease genetics.

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    Cell Genomics
    Article . 2023
    License: CC BY NC ND
    Data sources: Crossref
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    Europe PubMed Central
    Other literature type . 2023
    Data sources: PubMed Central
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      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Cell Genomicsarrow_drop_down
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      Cell Genomics
      Article . 2023
      License: CC BY NC ND
      Data sources: Crossref
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      Europe PubMed Central
      Other literature type . 2023
      Data sources: PubMed Central
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Georges Aad; S. Abdel Khalek; M. Abolins; Bobby Samir Acharya; +682 Authors

    A search for direct pair production of supersymmetric top squarks ((t) over tilde (1)) is presented, assuming the (t) over tilde (1) decays into a top quark and the lightest supersymmetric particle, (chi) over tilde (0)(1), and that both top quarks decay to purely hadronic final states. A total of 16 (4) events are observed compared to a predicted standard model background of 13.5(-3.6)(+3.7) (4.4(-1.3)(+1.7)) events in two signal regions based on integral Ldt = 4.7 fb(-1) of pp collision data taken at root s = 7 TeV with the ATLAS detector at the LHC. An exclusion region in the (t) over tilde (1) versus (chi) over tilde (0)(1) mass plane is evaluated: 370 1) 10) similar to 0 GeV while m((t) over tilde1) = 445 GeV is excluded for m((chi) over tilde 10) <= 50 GeV.

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    Physical Review Letters
    Article
    License: CC BY
    Data sources: UnpayWall
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    Physical Review Letters
    Article . 2012
    License: CC BY
    Data sources: Crossref
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      Physical Review Letters
      Article
      License: CC BY
      Data sources: UnpayWall
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      Physical Review Letters
      Article . 2012
      License: CC BY
      Data sources: Crossref
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Quentin Roy; Camelia Zakaria; Simon T. Perrault; Mathieu Nancel; +3 Authors

    Part 8: Pointing, Touch, Gesture and Speech-Based Interaction Techniques; International audience; Eyewear displays allow users to interact with virtual content displayed over real-world vision, in active situations like standing and walking. Pointing techniques for eyewear displays have been proposed, but their social acceptability, efficiency, and situation awareness remain to be assessed. Using a novel street-walking simulator, we conducted an empirical study of target acquisition while standing and walking under different levels of street crowdedness. We evaluated three phone-based eyewear pointing techniques: indirect touch on a touchscreen, and two in-air techniques using relative device rotations around forward and a downward axes. Direct touch on a phone, without eyewear, was used as a control condition. Results showed that indirect touch was the most efficient and socially acceptable technique, and that in-air pointing was inefficient when walking. Interestingly, the eyewear displays did not improve situation awareness compared to the control condition. We discuss implications for eyewear interaction design.

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    Preprint . Part of book or chapter of book
    License: CC BY
    Data sources: UnpayWall
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    https://doi.org/10.31219/osf.i...
    Preprint . 2019
    License: CC BY
    Data sources: Crossref
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    https://doi.org/10.1007/978-3-...
    Part of book or chapter of book . 2019
    License: Springer Nature TDM
    Data sources: Crossref
    Hal-Diderot
    Conference object . 2019
    License: CC BY
    Data sources: Hal-Diderot
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    Authors: Lin, Zheng Yan; Choi, Yong-Kab;

    AbstractIn this paper we establish large increment results and moduli of continuty for a two-parameter fractional Lévy Brownian motion on rectangles in the Euclidean plane via estimating upper bounds of large deviation probabilities on suprema of the two-parameter fractional Lévy Brownian motion.

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    Authors: Aaboud M.; Aad G.; Abbott B.; Abdinov O.; +1,011 Authors

    We thank CERN for the very successful operation of the LHC, as well as the support staff from our institutions without whom ATLAS could not be operated efficiently. We acknowledge the support of ANPCyT, Argentina; YerPhI, Armenia; ARC, Australia; BMWFW and FWF, Austria; ANAS, Azerbaijan; SSTC, Belarus; CNPq and FAPESP, Brazil; NSERC, NRC and CFI, Canada; CERN; CONICYT, Chile; CAS, MOST and NSFC, China; COLCIENCIAS, Colombia; MSMT CR, MPO CR and VSC CR, Czech Republic; DNRF and DNSRC, Denmark; IN2P3-CNRS, CEA-DRF/IRFU, France; SRNSFG, Georgia; BMBF, HGF, and MPG, Germany; GSRT, Greece; RGC, Hong Kong SAR, China; ISF and Benoziyo Center, Israel; INFN, Italy; MEXT and JSPS, Japan; CNRST, Morocco; NWO, Netherlands; RCN, Norway; MNiSW and NCN, Poland; FCT, Portugal; MNE/IFA, Romania; MES of Russia and NRC KI, Russian Federation; JINR; MESTD, Serbia; MSSR, Slovakia; ARRS and MIZS, Slovenia; DST/NRF, South Africa; MINECO, Spain; SRC and Wallenberg Foundation, Sweden; SERI, SNSF and Cantons of Bern and Geneva, Switzerland; MOST, Taiwan; TAEK, Turkey; STFC, United Kingdom; DOE and NSF, United States of America. In addition, individual groups and members have received support from BCKDF, CANARIE, CRC and Compute Canada, Canada; COST, ERC, ERDF, Horizon 2020, and Marie Sklodowska-Curie Actions, European Union; Investissements d' Avenir Labex and Idex, ANR, France; DFG and AvH Foundation, Germany; Herakleitos, Thales and Aristeia programmes co-financed by EU-ESF and the Greek NSRF, Greece; BSF-NSF and GIF, Israel; CERCA Programme Generalitat de Catalunya, Spain; The Royal Society and Leverhulme Trust, United Kingdom. The crucial computing support from all WLCG partners is acknowledged gratefully, in particular from CERN, the ATLAS Tier-1 facilities at TRIUMF (Canada), NDGF(Denmark, Norway, Sweden), CC-IN2P3 (France), KIT/GridKA (Germany), INFN-CNAF (Italy), NL-T1 (Netherlands), PIC (Spain), ASGC (Taiwan), RAL (UK) and BNL (USA), the Tier-2 facilities worldwide and large non-WLCG resource providers. Major contributors of comp Measurements of the azimuthal anisotropy in lead–lead collisions at sNN−−−√ = 5.02 TeV are presented using a data sample corresponding to 0.49 nb−1 integrated luminosity collected by the ATLAS experiment at the LHC in 2015. The recorded minimum-bias sample is enhanced by triggers for “ultra-central” collisions, providing an opportunity to perform detailed study of flow harmonics in the regime where the initial state is dominated by fluctuations. The anisotropy of the charged-particle azimuthal angle distributions is characterized by the Fourier coefficients, v2–v7, which are measured using the two-particle correlation, scalar-product and event-plane methods. The goal of the paper is to provide measurements of the differential as well as integrated flow harmonics vn over wide ranges of the transverse momentum, 0.5

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    CORE (RIOXX-UK Aggregator)
    Article . 2018
    License: CC BY
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    Repositório Comum
    Article . 2018
    Data sources: Repositório Comum
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    CERN Document Server
    Other literature type . 2018
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    Apollo
    Other literature type . 2018
    License: CC BY
    Data sources: Apollo
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    Apollo
    Article . 2019
    License: CC BY
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    DOAJ
    Article . 2018
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    https://doi.org/10.48550/arxiv...
    Article . 2018
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    Authors: Danielle M. Frechette; Alison L. Collins; James T. Harvey; Sean A. Hayes; +8 Authors

    AbstractAvian predation on juvenile salmonids is an important source of mortality in freshwater and estuarine habitats when birds and salmonids overlap spatially and temporally. We assessed the potential impact of avian predation upon juvenile steelhead Oncorhynchus mykiss in a coastal watershed in central California. We conducted stream surveys between 2008 and 2010 to determine the composition, distribution, and density of piscivorous birds in areas that provide rearing habitat for juvenile steelhead. The most commonly sighted bird species were common mergansers Mergus merganser and belted kingfishers Megacyrle alcyon. The density of avian predators varied spatially and temporally but was greatest in the estuary regardless of season and decreased with increasing distance from the estuary. In the absence of local predator diet data, we applied a bioenergetics model to estimate the potential predation on juvenile steelhead by mergansers and kingfishers in the Scott Creek estuary. Model parameters included (1) published values of bird energetic requirements and steelhead energy density, (2) the number of birds present in the estuary during the closure period (from stream surveys), and (3) the size frequency and abundance of steelhead present in the estuary during closure. We predicted the extent of predation for different values of steelhead in bird diets, accounting for uncertainty in the estimates using a Monte Carlo simulation approach. With the assumed contribution of steelhead to the diet ranging from 20% to 100%, the population of kingfishers foraging in the Scott Creek estuary had the potential to remove 3–17% of annual production, whereas mergansers had the potential to remove 5–54% of annual steelhead production. Our results suggest that predation by avian species, particularly mergansers, is an important source of mortality for threatened steelhead populations in central California and should be addressed in future salmonid research and recovery planning.Received February 13, 2013; accepted June 4, 2013

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    North American Journal of Fisheries Management
    Article . 2013
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      North American Journal of Fisheries Management
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  • Authors: Jorge E. Cortes; Jane F. Apperley; Elza Lomaia; Beatriz Moiraghi; +16 Authors

    7000 Background: PON, a third-generation tyrosine kinase inhibitor (TKI), demonstrated deep and long-lasting responses and survival in patients (pts) with chronic-phase chronic myeloid leukemia (CP-CML) resistant/intolerant to second-generation TKI therapy (PACE; NCT01207440); post hoc analysis suggested a relationship between dose and both adverse events and response. Here we present the primary analysis of OPTIC (NCT02467270), an ongoing, randomized, phase 2 trial with a novel response-based dosing regimen of PON in pts with resistant/intolerant CP-CML. Methods: Pts with CP-CML resistant/intolerant to ≥2 TKIs or with the BCR-ABL1 T315I mutation were randomized to PON starting doses of 45 mg (cohort A; 45 mg → 15 mg), 30 mg (B; 30 mg →15 mg), and 15 mg (C) once daily. Doses were reduced to 15 mg with achievement of ≤1% BCR-ABL1IS in cohorts A and B. The primary endpoint is ≤1% BCR-ABL1IS at 12 mo; secondary endpoints include cytogenetic and molecular responses and safety outcomes. AOEs were adjudicated prospectively by an independent review committee. Results: 283 pts were randomized (A/B/C: n=94/95/94) and had the following baseline characteristics: median age 48 y (18‒81 y); 98% received ≥2 (55% ≥3) TKIs; 99% had resistant disease; 40% had ≥1 baseline mutations (23% T315I). At the primary analysis with 32 mo median follow-up, 134 pts (47%; n=50/41/43) remained on treatment and 204 pts (72%) had PON exposure ≥12 mo. At 12 mo, 44% (41/93) in A, 29% (27/93) in B, and 23% (21/91) in C achieved ≤1% BCR-ABL1IS (Table); primary endpoint was met by cohort A. Dose reductions to 15 mg after achieving response (A/B) were 48/29%. Most common grades ≥3 TEAEs were thrombocytopenia, 27%; neutropenia, 17%; and anemia, 7%. AOEs/serious AOEs were reported in cohorts A (10%/4%), B (5%/4%), and C (3%/3%). Dose reductions or discontinuations for TEAEs (A/B/C) were 46/35/32% and 19/16/14%, respectively. Conclusions: The OPTIC primary analysis demonstrates the optimal benefit:risk profile for PON was achieved with a response-based dosing regimen starting with 45 mg/d, followed by dose reduction to 15 mg/d upon achieving ≤ 1% BCR-ABL1IS; 30 mg→15 mg and 15 mg cohorts may provide benefit, especially in pts without T315I mutation (Table). The observed ≤1% BCR-ABL1IS responses are supported by robust survival outcomes in pts with CP-CML resistant to second-generation BCR-ABL1 TKI therapy, both with and without BCR-ABL1 mutations. Clinical trial information: NCT02467270. [Table: see text]

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    Authors: Sumaiyah Mat; Pey June Tan; Chin Teck Ng; Farhana Fadzli; +4 Authors

    Osteoarthritis (OA) exacerbates skeletal muscle functioning, leading to postural instability and increased falls risk. However, the link between impaired physical function, OA and falls have not been elucidated. We investigated the role of impaired physical function as a potential mediator in the association between OA and falls. This study included 389 participants [229 fallers (≥2 falls or one injurious fall in the past 12 months), 160 non-fallers (no history of falls)], age (≥65 years) from a randomized controlled trial, the Malaysian Falls Assessment and Intervention Trial (MyFAIT). Physical function was assessed using Timed Up and Go (TUG) and Functional Reach (FR) tests. Knee and hip OA were diagnosed using three methods: Clinical, Radiological and Self-report. OA symptom severity was assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC). The total WOMAC score was categorized to asymptomatic, mild, moderate and severe symptoms. Individuals with radiological OA and 'mild' overall symptoms on the WOMAC score had reduced risk of falls compared to asymptomatic OA [OR: 0.402(0.172-0.940), p = 0.042]. Individuals with clinical OA and 'severe' overall symptoms had increased risk of falls compared to those with 'mild' OA [OR: 4.487(1.883-10.693), p = 0.005]. In individuals with radiological OA, mild symptoms appear protective of falls while those with clinical OA and severe symptoms have increased falls risk compared to those with mild symptoms. Both relationships between OA and falls were not mediated by physical limitations. Larger prospective studies are needed for further evaluation.

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    Europe PubMed Central
    Article . 2015
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    Article . 2015
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    Authors: Margaret Fast; Kelly Bunzeluk;

    Antimicrobial resistance (AMR) in bacteria is the end result of a multitude of factors. Some of the key factors beyond innate resistance include antimicrobial selective pressure (1–5), acquisition of a foreign genetic resistance element(s) (1–5), clonal dissemination (1) and new mutations (2,3,5); factors vary for different species and geographical locations. Increased global antimicrobial use is the foremost reason for the spread of AMR in the community setting (1). Social networks of individuals (households, schools and child care facilities) have served both as a reservoir for these bacteria and as a common route for their transmission. Similarly, hospitals, nursing homes and long-term care facilities have also served as reservoirs for antibiotic-resistant organisms, and the discharge of patients from these facilities contributes to the spread of resistance within communities. In addition, the use of antimicrobials in food animals has been an important contributing cause (1). In the preantibiotic era, the mortality of patients infected with Staphylococcus aureus bacteremia exceeded 80%. Although the introduction of penicillin in the early 1940s significantly improved the prognosis of patients with staphylococcal infection, penicillin-resistant staphylococci were recognized within two years of its use (4,6). More than 80% of both community- and hospital-acquired staphylococcal isolates were resistant to penicillin by the late 1960s. This transfer of resistance, from the hospital setting to communities, is a well-established pattern that recurs with each new wave of AMR (6). For example, the introduction of methicillin in 1961 was quickly followed by reports of methicillin-resistant isolates in hospitals, and is now seen regularly in community-based infections (6). Health care-associated strains of methicillin-resistant S aureus (HA-MRSA) have been known to cause a wide variety of infections (eg, wound infections, catheter-associated bacteremias or prosthesis infections). Community-acquired MRSA (CA-MRSA) has emerged as the causative agent of serious individual cases and outbreaks of skin and soft tissue infections and sepsis. Infections have been noted among those without the usual HA-MRSA risk factors (history of hospitalization or other institutionalization, antibiotic use, dialysis and chronic wounds), and outbreaks have been reported in well-defined epidemiological groups (children in child care facilities, athletes, military recruits and prison inmates) (1,7). CA-MRSA is distinguished from HA-MRSA, in part, by the type of staphylococcal chromosomal cassette – a mobile chromosomal element that carries the methicillin resistance gene mec. However, there is a progressive blurring of the two categories. HA-MRSA is also disseminated in the community (for example, MRSA has been transmitted from hospital patients to their household contacts), and CA-MRSA has entered health care settings and caused outbreaks in hospitals (1). Vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing organisms that are resistant to ceph-alosporins and monobactams, and penicillin-resistant Streptococcus pneumoniae have also evolved through a combination of acquired foreign genetic material, antibiotic selective pressure and clonal dissemination (1). Vancomycin-resistant enterococci have been associated with the use of growth promoters in food animals, especially in Europe (1), and extended-spectrum beta-lactamase-producing Gram negatives, especially Klebsiella and Escherichia coli, have been increasingly noted as a source of community-acquired infections (8). Similarly, penicillin-resistant S pneumoniae, a common cause of otitis media, sinusitis, community-acquired pneumonia, meningitis and bacteremia, has emerged in the past few decades – first identified more than 20 years after the introduction of penicillin (1,8). Although the ultimate impact of AMR in the community is still uncertain, reducing the development and limiting the spread of resistant organisms should be a public health priority. The two most urgent proven strategies to effect this goal are to limit antimicrobial use to prevent selective pressure, and to enhance infection prevention and control practices, including basic hand hygiene, to prevent clonal dissemination (1,2,9,10). Several national and regional groups in Canada are currently investigating AMR issues, and numerous policy and practice guidance documents have been produced. Despite these efforts, public health leaders and practitioners across Canada have argued that knowledge and practice gaps still exist on the issue of AMR, particularly in community settings. With the assistance of an expert advisory group, the National Collaborating Centre for Infectious Diseases (NCCID) identified projects that could help reduce the burden of community-acquired AMR in Canada. The goal of one project was to describe population-level interventions to reduce the development and transmission of community-associated AMR. NCCID issued a call for proposals in the summer of 2008, and in the fall of 2008, a selection process was undertaken that included peer review by independent, external experts. Three proposals were selected for NCCID funding: Antimicrobial use and resistance in pigs and chickens: A review of the science, policy and control practices from farm to slaughter – Leigh B Rosengren, Sheryl P Gow and J Scott Weese. A review of alternative practices to antimicrobial use for disease control in the commercial feedlot – Carl S Ribble, Tyler Stitt, S Iwasawa, Lorraine Toews and Craig Stephen. Strategies to control community-associated antimicrobial resistance among enteric bacteria and methicillin-resistant Staphylococcus aureus in Canada – Jeff Wilson, John Conly, Thomas Wong, Gayatri Jayaraman, Jan Sargeant, Andrew Papadopoulos, Virginia Young, Melanie Quist-Moyer and Sharon Bauer. Drafts of the comprehensive reviews were read by a minimum of five independent reviewers. Feedback was compiled and provided to the authors for incorporation. The authors presented their general findings at a community-acquired AMR consultation hosted by the NCCID in February 2010. The consultation, which included 50 experts from human, animal and environmental health fields, allowed the reviews to be further refined. Proceedings from the consultation are available on the NCCID website (www.nccid.ca/en/caamr-consultation-feb10). The subsequent pages present the executive summaries of the three reviews (the full comprehensive reviews are available online at http://nccid.ca/en/amr-reviews). The first two reviews focus on antimicrobial use and resistance in animals raised for food, namely pigs and chickens (11) and cattle (12). The third review discusses strategies to control community-acquired AMR among human enteric bacteria and MRSA (7). It is hoped that these papers will lead to further discussion and research into the most effective strategies to reduce the development and spread of AMR.

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  • Authors: G, Remington; J, Lee; O, Agid; H, Takeuchi; +5 Authors

    Clozapine was first introduced as an antipsychotic in the 1970's but a cluster of deaths, later linked to the drug's risk of agranulocytosis, led to its withdrawal in most countries. However, work in the 1980's established its unique efficacy in treatment resistant schizophrenia (TRS), which constitutes as many as 30% of those with the illness. Clozapine was reintroduced with this indication shortly thereafter, but because of this risk its use requires routine hematologic monitoring.An update is provided regarding clozapine's risk of neutropenia, agranulocytosis, and associated mortality. In addition, updates are provided on other side effects, specifically myocarditis and bowel obstruction, as evidence suggests these are more common than agranulocytosis and associated with higher mortality rates.Clozapine remains the only treatment indicated in TRS, but it is dramatically underutilized. Clearly there are serious side effects associated with its use, and while the focus has historically been on hematologic concerns, we highlight other side effects that also demand systematic monitoring. Because it is the only effective treatment option we have for TRS, though, efforts must be implemented that ensure its use in this population while maximizing safety.

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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Marisa C. Hamilton; James D. Fife; Ersin Akinci; Tian Yu; +13 Authors

    SummaryGenetic variation contributes greatly to LDL cholesterol (LDL-C) levels and coronary artery disease risk. By combining analysis of rare coding variants from the UK Biobank and genome-scale CRISPR-Cas9 knockout and activation screening, we have substantially improved the identification of genes whose disruption alters serum LDL-C levels. We identify 21 genes in which rare coding variants significantly alter LDL-C levels at least partially through altered LDL-C uptake. We use co-essentiality-based gene module analysis to show that dysfunction of the RAB10 vesicle transport pathway leads to hypercholesterolemia in humans and mice by impairing surface LDL receptor levels. Further, we demonstrate that loss of function ofOTX2leads to robust reduction in serum LDL-C levels in mice and humans by increasing cellular LDL-C uptake. Altogether, we present an integrated approach that improves our understanding of genetic regulators of LDL-C levels and provides a roadmap for further efforts to dissect complex human disease genetics.

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    Cell Genomics
    Article . 2023
    License: CC BY NC ND
    Data sources: Crossref
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    Europe PubMed Central
    Other literature type . 2023
    Data sources: PubMed Central
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      Cell Genomics
      Article . 2023
      License: CC BY NC ND
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      Europe PubMed Central
      Other literature type . 2023
      Data sources: PubMed Central
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    Authors: Georges Aad; S. Abdel Khalek; M. Abolins; Bobby Samir Acharya; +682 Authors

    A search for direct pair production of supersymmetric top squarks ((t) over tilde (1)) is presented, assuming the (t) over tilde (1) decays into a top quark and the lightest supersymmetric particle, (chi) over tilde (0)(1), and that both top quarks decay to purely hadronic final states. A total of 16 (4) events are observed compared to a predicted standard model background of 13.5(-3.6)(+3.7) (4.4(-1.3)(+1.7)) events in two signal regions based on integral Ldt = 4.7 fb(-1) of pp collision data taken at root s = 7 TeV with the ATLAS detector at the LHC. An exclusion region in the (t) over tilde (1) versus (chi) over tilde (0)(1) mass plane is evaluated: 370 1) 10) similar to 0 GeV while m((t) over tilde1) = 445 GeV is excluded for m((chi) over tilde 10) <= 50 GeV.

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    Physical Review Letters
    Article
    License: CC BY
    Data sources: UnpayWall
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    Physical Review Letters
    Article . 2012
    License: CC BY
    Data sources: Crossref
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      Physical Review Letters
      Article
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      Physical Review Letters
      Article . 2012
      License: CC BY
      Data sources: Crossref
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Quentin Roy; Camelia Zakaria; Simon T. Perrault; Mathieu Nancel; +3 Authors

    Part 8: Pointing, Touch, Gesture and Speech-Based Interaction Techniques; International audience; Eyewear displays allow users to interact with virtual content displayed over real-world vision, in active situations like standing and walking. Pointing techniques for eyewear displays have been proposed, but their social acceptability, efficiency, and situation awareness remain to be assessed. Using a novel street-walking simulator, we conducted an empirical study of target acquisition while standing and walking under different levels of street crowdedness. We evaluated three phone-based eyewear pointing techniques: indirect touch on a touchscreen, and two in-air techniques using relative device rotations around forward and a downward axes. Direct touch on a phone, without eyewear, was used as a control condition. Results showed that indirect touch was the most efficient and socially acceptable technique, and that in-air pointing was inefficient when walking. Interestingly, the eyewear displays did not improve situation awareness compared to the control condition. We discuss implications for eyewear interaction design.

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    https://hal.archives-ouvertes....
    Preprint . Part of book or chapter of book
    License: CC BY
    Data sources: UnpayWall
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    https://doi.org/10.31219/osf.i...
    Preprint . 2019
    License: CC BY
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    https://doi.org/10.1007/978-3-...
    Part of book or chapter of book . 2019
    License: Springer Nature TDM
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    Hal-Diderot
    Conference object . 2019
    License: CC BY
    Data sources: Hal-Diderot
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    Authors: Lin, Zheng Yan; Choi, Yong-Kab;

    AbstractIn this paper we establish large increment results and moduli of continuty for a two-parameter fractional Lévy Brownian motion on rectangles in the Euclidean plane via estimating upper bounds of large deviation probabilities on suprema of the two-parameter fractional Lévy Brownian motion.

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    Authors: Aaboud M.; Aad G.; Abbott B.; Abdinov O.; +1,011 Authors

    We thank CERN for the very successful operation of the LHC, as well as the support staff from our institutions without whom ATLAS could not be operated efficiently. We acknowledge the support of ANPCyT, Argentina; YerPhI, Armenia; ARC, Australia; BMWFW and FWF, Austria; ANAS, Azerbaijan; SSTC, Belarus; CNPq and FAPESP, Brazil; NSERC, NRC and CFI, Canada; CERN; CONICYT, Chile; CAS, MOST and NSFC, China; COLCIENCIAS, Colombia; MSMT CR, MPO CR and VSC CR, Czech Republic; DNRF and DNSRC, Denmark; IN2P3-CNRS, CEA-DRF/IRFU, France; SRNSFG, Georgia; BMBF, HGF, and MPG, Germany; GSRT, Greece; RGC, Hong Kong SAR, China; ISF and Benoziyo Center, Israel; INFN, Italy; MEXT and JSPS, Japan; CNRST, Morocco; NWO, Netherlands; RCN, Norway; MNiSW and NCN, Poland; FCT, Portugal; MNE/IFA, Romania; MES of Russia and NRC KI, Russian Federation; JINR; MESTD, Serbia; MSSR, Slovakia; ARRS and MIZS, Slovenia; DST/NRF, South Africa; MINECO, Spain; SRC and Wallenberg Foundation, Sweden; SERI, SNSF and Cantons of Bern and Geneva, Switzerland; MOST, Taiwan; TAEK, Turkey; STFC, United Kingdom; DOE and NSF, United States of America. In addition, individual groups and members have received support from BCKDF, CANARIE, CRC and Compute Canada, Canada; COST, ERC, ERDF, Horizon 2020, and Marie Sklodowska-Curie Actions, European Union; Investissements d' Avenir Labex and Idex, ANR, France; DFG and AvH Foundation, Germany; Herakleitos, Thales and Aristeia programmes co-financed by EU-ESF and the Greek NSRF, Greece; BSF-NSF and GIF, Israel; CERCA Programme Generalitat de Catalunya, Spain; The Royal Society and Leverhulme Trust, United Kingdom. The crucial computing support from all WLCG partners is acknowledged gratefully, in particular from CERN, the ATLAS Tier-1 facilities at TRIUMF (Canada), NDGF(Denmark, Norway, Sweden), CC-IN2P3 (France), KIT/GridKA (Germany), INFN-CNAF (Italy), NL-T1 (Netherlands), PIC (Spain), ASGC (Taiwan), RAL (UK) and BNL (USA), the Tier-2 facilities worldwide and large non-WLCG resource providers. Major contributors of comp Measurements of the azimuthal anisotropy in lead–lead collisions at sNN−−−√ = 5.02 TeV are presented using a data sample corresponding to 0.49 nb−1 integrated luminosity collected by the ATLAS experiment at the LHC in 2015. The recorded minimum-bias sample is enhanced by triggers for “ultra-central” collisions, providing an opportunity to perform detailed study of flow harmonics in the regime where the initial state is dominated by fluctuations. The anisotropy of the charged-particle azimuthal angle distributions is characterized by the Fourier coefficients, v2–v7, which are measured using the two-particle correlation, scalar-product and event-plane methods. The goal of the paper is to provide measurements of the differential as well as integrated flow harmonics vn over wide ranges of the transverse momentum, 0.5

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    CORE (RIOXX-UK Aggregator)
    Article . 2018
    License: CC BY
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    Repositório Comum
    Article . 2018
    Data sources: Repositório Comum
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    CERN Document Server
    Other literature type . 2018
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    Apollo
    Other literature type . 2018
    License: CC BY
    Data sources: Apollo
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    Apollo
    Article . 2019
    License: CC BY
    Data sources: Datacite
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    DOAJ
    Article . 2018
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    https://doi.org/10.48550/arxiv...
    Article . 2018
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    Authors: Danielle M. Frechette; Alison L. Collins; James T. Harvey; Sean A. Hayes; +8 Authors

    AbstractAvian predation on juvenile salmonids is an important source of mortality in freshwater and estuarine habitats when birds and salmonids overlap spatially and temporally. We assessed the potential impact of avian predation upon juvenile steelhead Oncorhynchus mykiss in a coastal watershed in central California. We conducted stream surveys between 2008 and 2010 to determine the composition, distribution, and density of piscivorous birds in areas that provide rearing habitat for juvenile steelhead. The most commonly sighted bird species were common mergansers Mergus merganser and belted kingfishers Megacyrle alcyon. The density of avian predators varied spatially and temporally but was greatest in the estuary regardless of season and decreased with increasing distance from the estuary. In the absence of local predator diet data, we applied a bioenergetics model to estimate the potential predation on juvenile steelhead by mergansers and kingfishers in the Scott Creek estuary. Model parameters included (1) published values of bird energetic requirements and steelhead energy density, (2) the number of birds present in the estuary during the closure period (from stream surveys), and (3) the size frequency and abundance of steelhead present in the estuary during closure. We predicted the extent of predation for different values of steelhead in bird diets, accounting for uncertainty in the estimates using a Monte Carlo simulation approach. With the assumed contribution of steelhead to the diet ranging from 20% to 100%, the population of kingfishers foraging in the Scott Creek estuary had the potential to remove 3–17% of annual production, whereas mergansers had the potential to remove 5–54% of annual steelhead production. Our results suggest that predation by avian species, particularly mergansers, is an important source of mortality for threatened steelhead populations in central California and should be addressed in future salmonid research and recovery planning.Received February 13, 2013; accepted June 4, 2013

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    North American Journal of Fisheries Management
    Article . 2013
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      North American Journal of Fisheries Management
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  • Authors: Jorge E. Cortes; Jane F. Apperley; Elza Lomaia; Beatriz Moiraghi; +16 Authors

    7000 Background: PON, a third-generation tyrosine kinase inhibitor (TKI), demonstrated deep and long-lasting responses and survival in patients (pts) with chronic-phase chronic myeloid leukemia (CP-CML) resistant/intolerant to second-generation TKI therapy (PACE; NCT01207440); post hoc analysis suggested a relationship between dose and both adverse events and response. Here we present the primary analysis of OPTIC (NCT02467270), an ongoing, randomized, phase 2 trial with a novel response-based dosing regimen of PON in pts with resistant/intolerant CP-CML. Methods: Pts with CP-CML resistant/intolerant to ≥2 TKIs or with the BCR-ABL1 T315I mutation were randomized to PON starting doses of 45 mg (cohort A; 45 mg → 15 mg), 30 mg (B; 30 mg →15 mg), and 15 mg (C) once daily. Doses were reduced to 15 mg with achievement of ≤1% BCR-ABL1IS in cohorts A and B. The primary endpoint is ≤1% BCR-ABL1IS at 12 mo; secondary endpoints include cytogenetic and molecular responses and safety outcomes. AOEs were adjudicated prospectively by an independent review committee. Results: 283 pts were randomized (A/B/C: n=94/95/94) and had the following baseline characteristics: median age 48 y (18‒81 y); 98% received ≥2 (55% ≥3) TKIs; 99% had resistant disease; 40% had ≥1 baseline mutations (23% T315I). At the primary analysis with 32 mo median follow-up, 134 pts (47%; n=50/41/43) remained on treatment and 204 pts (72%) had PON exposure ≥12 mo. At 12 mo, 44% (41/93) in A, 29% (27/93) in B, and 23% (21/91) in C achieved ≤1% BCR-ABL1IS (Table); primary endpoint was met by cohort A. Dose reductions to 15 mg after achieving response (A/B) were 48/29%. Most common grades ≥3 TEAEs were thrombocytopenia, 27%; neutropenia, 17%; and anemia, 7%. AOEs/serious AOEs were reported in cohorts A (10%/4%), B (5%/4%), and C (3%/3%). Dose reductions or discontinuations for TEAEs (A/B/C) were 46/35/32% and 19/16/14%, respectively. Conclusions: The OPTIC primary analysis demonstrates the optimal benefit:risk profile for PON was achieved with a response-based dosing regimen starting with 45 mg/d, followed by dose reduction to 15 mg/d upon achieving ≤ 1% BCR-ABL1IS; 30 mg→15 mg and 15 mg cohorts may provide benefit, especially in pts without T315I mutation (Table). The observed ≤1% BCR-ABL1IS responses are supported by robust survival outcomes in pts with CP-CML resistant to second-generation BCR-ABL1 TKI therapy, both with and without BCR-ABL1 mutations. Clinical trial information: NCT02467270. [Table: see text]

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    Authors: Sumaiyah Mat; Pey June Tan; Chin Teck Ng; Farhana Fadzli; +4 Authors

    Osteoarthritis (OA) exacerbates skeletal muscle functioning, leading to postural instability and increased falls risk. However, the link between impaired physical function, OA and falls have not been elucidated. We investigated the role of impaired physical function as a potential mediator in the association between OA and falls. This study included 389 participants [229 fallers (≥2 falls or one injurious fall in the past 12 months), 160 non-fallers (no history of falls)], age (≥65 years) from a randomized controlled trial, the Malaysian Falls Assessment and Intervention Trial (MyFAIT). Physical function was assessed using Timed Up and Go (TUG) and Functional Reach (FR) tests. Knee and hip OA were diagnosed using three methods: Clinical, Radiological and Self-report. OA symptom severity was assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC). The total WOMAC score was categorized to asymptomatic, mild, moderate and severe symptoms. Individuals with radiological OA and 'mild' overall symptoms on the WOMAC score had reduced risk of falls compared to asymptomatic OA [OR: 0.402(0.172-0.940), p = 0.042]. Individuals with clinical OA and 'severe' overall symptoms had increased risk of falls compared to those with 'mild' OA [OR: 4.487(1.883-10.693), p = 0.005]. In individuals with radiological OA, mild symptoms appear protective of falls while those with clinical OA and severe symptoms have increased falls risk compared to those with mild symptoms. Both relationships between OA and falls were not mediated by physical limitations. Larger prospective studies are needed for further evaluation.

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    Europe PubMed Central
    Article . 2015
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    Article . 2015
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    Authors: Margaret Fast; Kelly Bunzeluk;

    Antimicrobial resistance (AMR) in bacteria is the end result of a multitude of factors. Some of the key factors beyond innate resistance include antimicrobial selective pressure (1–5), acquisition of a foreign genetic resistance element(s) (1–5), clonal dissemination (1) and new mutations (2,3,5); factors vary for different species and geographical locations. Increased global antimicrobial use is the foremost reason for the spread of AMR in the community setting (1). Social networks of individuals (households, schools and child care facilities) have served both as a reservoir for these bacteria and as a common route for their transmission. Similarly, hospitals, nursing homes and long-term care facilities have also served as reservoirs for antibiotic-resistant organisms, and the discharge of patients from these facilities contributes to the spread of resistance within communities. In addition, the use of antimicrobials in food animals has been an important contributing cause (1). In the preantibiotic era, the mortality of patients infected with Staphylococcus aureus bacteremia exceeded 80%. Although the introduction of penicillin in the early 1940s significantly improved the prognosis of patients with staphylococcal infection, penicillin-resistant staphylococci were recognized within two years of its use (4,6). More than 80% of both community- and hospital-acquired staphylococcal isolates were resistant to penicillin by the late 1960s. This transfer of resistance, from the hospital setting to communities, is a well-established pattern that recurs with each new wave of AMR (6). For example, the introduction of methicillin in 1961 was quickly followed by reports of methicillin-resistant isolates in hospitals, and is now seen regularly in community-based infections (6). Health care-associated strains of methicillin-resistant S aureus (HA-MRSA) have been known to cause a wide variety of infections (eg, wound infections, catheter-associated bacteremias or prosthesis infections). Community-acquired MRSA (CA-MRSA) has emerged as the causative agent of serious individual cases and outbreaks of skin and soft tissue infections and sepsis. Infections have been noted among those without the usual HA-MRSA risk factors (history of hospitalization or other institutionalization, antibiotic use, dialysis and chronic wounds), and outbreaks have been reported in well-defined epidemiological groups (children in child care facilities, athletes, military recruits and prison inmates) (1,7). CA-MRSA is distinguished from HA-MRSA, in part, by the type of staphylococcal chromosomal cassette – a mobile chromosomal element that carries the methicillin resistance gene mec. However, there is a progressive blurring of the two categories. HA-MRSA is also disseminated in the community (for example, MRSA has been transmitted from hospital patients to their household contacts), and CA-MRSA has entered health care settings and caused outbreaks in hospitals (1). Vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing organisms that are resistant to ceph-alosporins and monobactams, and penicillin-resistant Streptococcus pneumoniae have also evolved through a combination of acquired foreign genetic material, antibiotic selective pressure and clonal dissemination (1). Vancomycin-resistant enterococci have been associated with the use of growth promoters in food animals, especially in Europe (1), and extended-spectrum beta-lactamase-producing Gram negatives, especially Klebsiella and Escherichia coli, have been increasingly noted as a source of community-acquired infections (8). Similarly, penicillin-resistant S pneumoniae, a common cause of otitis media, sinusitis, community-acquired pneumonia, meningitis and bacteremia, has emerged in the past few decades – first identified more than 20 years after the introduction of penicillin (1,8). Although the ultimate impact of AMR in the community is still uncertain, reducing the development and limiting the spread of resistant organisms should be a public health priority. The two most urgent proven strategies to effect this goal are to limit antimicrobial use to prevent selective pressure, and to enhance infection prevention and control practices, including basic hand hygiene, to prevent clonal dissemination (1,2,9,10). Several national and regional groups in Canada are currently investigating AMR issues, and numerous policy and practice guidance documents have been produced. Despite these efforts, public health leaders and practitioners across Canada have argued that knowledge and practice gaps still exist on the issue of AMR, particularly in community settings. With the assistance of an expert advisory group, the National Collaborating Centre for Infectious Diseases (NCCID) identified projects that could help reduce the burden of community-acquired AMR in Canada. The goal of one project was to describe population-level interventions to reduce the development and transmission of community-associated AMR. NCCID issued a call for proposals in the summer of 2008, and in the fall of 2008, a selection process was undertaken that included peer review by independent, external experts. Three proposals were selected for NCCID funding: Antimicrobial use and resistance in pigs and chickens: A review of the science, policy and control practices from farm to slaughter – Leigh B Rosengren, Sheryl P Gow and J Scott Weese. A review of alternative practices to antimicrobial use for disease control in the commercial feedlot – Carl S Ribble, Tyler Stitt, S Iwasawa, Lorraine Toews and Craig Stephen. Strategies to control community-associated antimicrobial resistance among enteric bacteria and methicillin-resistant Staphylococcus aureus in Canada – Jeff Wilson, John Conly, Thomas Wong, Gayatri Jayaraman, Jan Sargeant, Andrew Papadopoulos, Virginia Young, Melanie Quist-Moyer and Sharon Bauer. Drafts of the comprehensive reviews were read by a minimum of five independent reviewers. Feedback was compiled and provided to the authors for incorporation. The authors presented their general findings at a community-acquired AMR consultation hosted by the NCCID in February 2010. The consultation, which included 50 experts from human, animal and environmental health fields, allowed the reviews to be further refined. Proceedings from the consultation are available on the NCCID website (www.nccid.ca/en/caamr-consultation-feb10). The subsequent pages present the executive summaries of the three reviews (the full comprehensive reviews are available online at http://nccid.ca/en/amr-reviews). The first two reviews focus on antimicrobial use and resistance in animals raised for food, namely pigs and chickens (11) and cattle (12). The third review discusses strategies to control community-acquired AMR among human enteric bacteria and MRSA (7). It is hoped that these papers will lead to further discussion and research into the most effective strategies to reduce the development and spread of AMR.

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