155 research outputs found

    Genome-scale reconstruction of the metabolic network in Yersinia pestis, strain 91001

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    The gram-negative bacterium Yersinia pestis, the aetiological agent of bubonic plague, is one the deadliest pathogens known to man. Despite its historical reputation, plague is a modern disease which annually afflicts thousands of people. Public safety considerations greatly limit clinical experimentation on this organism and thus development of theoretical tools to analyze the capabilities of this pathogen is of utmost importance. Here, we report the first genome-scale metabolic model of Yersinia pestis biovar Mediaevalis based both on its recently annotated genome, and physiological and biochemical data from literature. Our model demonstrates excellent agreement with Y. pestis known metabolic needs and capabilities. Since Y. pestis is a meiotrophic organism, we have developed CryptFind, a systematic approach to identify all candidate cryptic genes responsible for known and theoretical meiotrophic phenomena. In addition to uncovering every known cryptic gene for Y. pestis, our analysis of the rhamnose fermentation pathway suggests that betB is the responsible cryptic gene. Despite all of our medical advances, we still do not have a vaccine for bubonic plague. Recent discoveries of antibiotic resistant strains of Yersinia pestis coupled with the threat of plague being used as a bioterrorism weapon compel us to develop new tools for studying the physiology of this deadly pathogen. Using our theoretical model, we can study the cells phenotypic behavior under different circumstances and identify metabolic weaknesses which may be harnessed for the development of therapeutics. Additionally, the automatic identification of cryptic genes expands the usage of genomic data for pharmaceutical purposes.Comment: 27 pages, 4 figures, 3 table

    PREDICT-CP: study protocol of implementation of comprehensive surveillance to predict outcomes for school-aged children with cerebral palsy

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    Objectives: Cerebral palsy (CP) remains the world’s most common childhood physical disability with total annual costs of care and lost well-being of $A3.87b. The PREDICT-CP (NHMRC 1077257 Partnership Project: Comprehensive surveillance to PREDICT outcomes for school age children with CP) study will investigate the influence of brain structure, body composition, dietary intake, oropharyngeal function, habitual physical activity, musculoskeletal development (hip status, bone health) and muscle performance on motor attainment, cognition, executive function, communication, participation, quality of life and related health resource use costs. The PREDICT-CP cohort provides further follow-up at 8–12 years of two overlapping preschool-age cohorts examined from 1.5 to 5 years (NHMRC 465128 motor and brain development; NHMRC 569605 growth, nutrition and physical activity). Methods and analyses: This population-based cohort study undertakes state-wide surveillance of 245 children with CP born in Queensland (birth years 2006–2009). Children will be classified for Gross Motor Function Classification System; Manual Ability Classification System, Communication Function Classification System and Eating and Drinking Ability Classification System. Outcomes include gross motor function, musculoskeletal development (hip displacement, spasticity, muscle contracture), upper limb function, communication difficulties, oropharyngeal dysphagia, dietary intake and body composition, participation, parent-reported and child-reported quality of life and medical and allied health resource use. These detailed phenotypical data will be compared with brain macrostructure and microstructure using 3 Tesla MRI (3T MRI). Relationships between brain lesion severity and outcomes will be analysed using multilevel mixed-effects models. Ethics and dissemination: The PREDICT-CP protocol is a prospectively registered and ethically accepted study protocol. The study combines data at 1.5–5 then 8–12 years of direct clinical assessment to enable prediction of outcomes and healthcare needs essential for tailoring interventions (eg, rehabilitation, orthopaedic surgery and nutritional supplements) and the projected healthcare utilisation

    On the origin of glioma

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    Glioma is the most frequent primary brain tumor of adults that has a presumably glial origin. Although our knowledge regarding molecular mechanisms and signaling pathways involved in gliomagenesis has increased immensely during the past decade, high-grade glioma remains a lethal disease with dismal prognosis. The failure of current therapies has to a large extent been ascribed the functional heterogeneity of glioma cells. One reason for this heterogeneity is most certainly the large number of variations in genetic alterations that can be found in high-grade gliomas. Another factor that may influence glioma heterogeneity could be the cell type from which the glioma is initiated. The cell of origin for glioma is still undefined, and additional knowledge about this issue may prove critical for a more complete understanding of glioma biology. Based on information from patients, developmental biology, and experimental glioma models, the most putative target cells include astrocytes, neural stem cells, and oligodendrocyte precursor cells, which are all discussed in more detail in this article. Animal modeling of glioma suggests that these three cell types have the capability to be the origin of glioma, and we have reason to believe that, depending on the initiating cell type, prognosis and response to therapy may be significantly different. Thus, it is essential to explore further the role of cellular origin in glioma

    Anxiety profiles and protective factors: A latent profile analysis in children

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    The current study investigated the presence of different anxiety profiles in schoolchildren in order to understand whether Mathematics and Test Anxiety are a manifestation of a general form of anxiety, or the expression of specific forms of anxiety. Moreover, we also examined the influence of personal protective factors. The results of a latent profile analysis, conducted on 664 children attending grades 3 to 6, clearly identified three different profiles distinguished on the basis of the level of general, test and mathematics anxiety. Protective factors, such as self-concept and resilience, were differently related to anxiety: the former was clearly lower when the risk profile was higher, whereas students were able to maintain a certain level of resilience up to an average risk of developing forms of anxiety. The implications of these findings may lead to the development of specific intervention programs aimed at reducing students’ anxiety and fostering self-concept and resilience. © 2017 Elsevier Lt

    BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

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    Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

    Regional Practice Variation and Outcomes in the Standard Versus Accelerated Initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) Trial: A Post Hoc Secondary Analysis

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    OBJECTIVES: Among patients with severe acute kidney injury (AKI) admitted to the ICU in high-income countries, regional practice variations for fluid balance (FB) management, timing, and choice of renal replacement therapy (RRT) modality may be significant. DESIGN: Secondary post hoc analysis of the STandard vs. Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial (ClinicalTrials.gov number NCT02568722). SETTING: One hundred-fifty-three ICUs in 13 countries. PATIENTS: Altogether 2693 critically ill patients with AKI, of whom 994 were North American, 1143 European, and 556 from Australia and New Zealand (ANZ). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Total mean FB to a maximum of 14 days was +7199 mL in North America, +5641 mL in Europe, and +2211 mL in ANZ (p < 0.001). The median time to RRT initiation among patients allocated to the standard strategy was longest in Europe compared with North America and ANZ (p < 0.001; p < 0.001). Continuous RRT was the initial RRT modality in 60.8% of patients in North America and 56.8% of patients in Europe, compared with 96.4% of patients in ANZ (p < 0.001). After adjustment for predefined baseline characteristics, compared with North American and European patients, those in ANZ were more likely to survive to ICU (p < 0.001) and hospital discharge (p < 0.001) and to 90 days (for ANZ vs. Europe: risk difference [RD], -11.3%; 95% CI, -17.7% to -4.8%; p < 0.001 and for ANZ vs. North America: RD, -10.3%; 95% CI, -17.5% to -3.1%; p = 0.007). CONCLUSIONS: Among STARRT-AKI trial centers, significant regional practice variation exists regarding FB, timing of initiation of RRT, and initial use of continuous RRT. After adjustment, such practice variation was associated with lower ICU and hospital stay and 90-day mortality among ANZ patients compared with other regions

    Whole-genome sequencing reveals host factors underlying critical COVID-19