rEHR: An R package for manipulating and analysing Electronic Health Record data

Research with structured Electronic Health Records (EHRs) is expanding as data becomes more accessible; analytic methods advance; and the scientific validity of such studies is increasingly accepted. However, data science methodology to enable the rapid searching/extraction, cleaning and analysis of these large, often complex, datasets is less well developed. In addition, commonly used software is inadequate, resulting in bottlenecks in research workflows and in obstacles to increased transparency and reproducibility of the research. Preparing a research-ready dataset from EHRs is a complex and time consuming task requiring substantial data science skills, even for simple designs. In addition, certain aspects of the workflow are computationally intensive, for example extraction of longitudinal data and matching controls to a large cohort, which may take days or even weeks to run using standard software. The rEHR package simplifies and accelerates the process of extracting ready-for-analysis datasets from EHR databases. It has a simple import function to a database backend that greatly accelerates data access times. A set of generic query functions allow users to extract data efficiently without needing detailed knowledge of SQL queries. Longitudinal data extractions can also be made in a single command, making use of parallel processing. The package also contains functions for cutting data by time-varying covariates, matching controls to cases, unit conversion and construction of clinical code lists. There are also functions to synthesise dummy EHR. The package has been tested with one for the largest primary care EHRs, the Clinical Practice Research Datalink (CPRD), but allows for a common interface to other EHRs. This simplified and accelerated work flow for EHR data extraction results in simpler, cleaner scripts that are more easily debugged, shared and reproduced

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

The individual and combined effects of obesity- and ageing-induced systemic inflammation on human skeletal muscle properties.

BACKGROUND/OBJECTIVES: The purpose of this study was to determine whether circulating pro-inflammatory cytokines, elevated with increased fat mass and ageing, were associated with muscle properties in young and older people with variable adiposity. SUBJECTS/METHODS: Seventy-five young (18-49 yrs) and 67 older (50-80 yrs) healthy, untrained men and women (BMI: 17-49 kg/m(2)) performed isometric and isokinetic plantar flexor maximum voluntary contractions (MVCs). Volume (Vm), fascicle pennation angle (FPA), and physiological cross-sectional area (PCSA) of the gastrocnemius medialis (GM) muscle were measured using ultrasonography. Voluntary muscle activation (VA) was assessed using electrical stimulation. GM specific force was calculated as GM fascicle force/PCSA. Percentage body fat (BF%), body fat mass (BFM), and lean mass (BLM) were assessed using dual-energy X-ray absorptiometry. Serum concentration of 12 cytokines was measured using multiplex luminometry. RESULTS: Despite greater Vm, FPA, and PCSA (P0.05), while IL-8 correlated with VA in older but not young adults (r⩾0.378, P⩽0.027). TNF-alpha correlated with MVC, lean mass, GM FPA and maximum force in older adults (r⩾0.458; P⩽0.048). CONCLUSIONS: The age- and adiposity-dependent relationships found here provide evidence that circulating pro-inflammatory cytokines may play different roles in muscle remodelling according to the age and adiposity of the individual.International Journal of Obesity accepted article preview online, 29 August 2016. doi:10.1038/ijo.2016.151

Situational awareness, relational coordination and integrated care delivery to hospitalized elderly in the Netherlands: A comparison between hospitals

__Abstract__ Background: It is known that interprofessional collaboration is crucial for integrated care delivery, yet we are still unclear about the underlying mechanisms explaining effectiveness of integrated care delivery to older patients. In addition, we lack research comparing integrated care delivery between hospitals. Therefore, this study aims to (i) provide insight into the underlying components 'relational coordination' and 'situational awareness' of integrated care delivery and the role of team and organizational context in integrated care delivery; and (ii) compare situational awareness, relational coordination, and integrated care delivery of different hospitals in the Netherlands. Methods. This cross-sectional study took place in 2012 among professionals from three different hospitals involved in the delivery of care to older patients. A total of 215 professionals filled in the questionnaire (42% response rate).Descriptive statistics and paired-sample t-tests were used to investigate the level of situational awareness, relational coordination, and integrated care delivery in the three different hospitals. Correlation and multilevel analyses were used to investigate the relationship between background characteristics, team context, organizational context, situational awareness, relational coordination and integrated care delivery. Results: No differences in background characteristics, team context, organizational context, situational awareness, relational coordination and integrated care delivery were found among the three hospitals. Correlational analysis revealed that situational awareness (r = 0.30; p < 0.01), relational coordination (r = 0.17; p < 0.05), team climate (r = 0.29; p < 0.01), formal internal communication (r = 0.46; p < 0.01), and informal internal communication (r = 0.36; p < 0.01) were positively associated with integrated care delivery. Stepwise multilevel analyses showed that formal internal communication (p < 0.001) and situational awareness (p < 0.01) were associated with integrated care delivery. Team climate was not significantly associated with integrated care delivery when situational awareness and relational coordination were included in the equation. Thus situational awareness acted as mediator between team climate and integrated care delivery among professionals delivering care to older hospitalized patients. Conclusions: The results of this study show the importance of formal internal communication and situational awareness for quality of care delivery to hospitalized older patients

Treatment of neuromyelitis optica: state-of-the-art and emerging therapies.

Neuromyelitis optica (NMO) is an autoimmune disease of the CNS that is characterized by inflammatory demyelinating lesions in the spinal cord and optic nerve, potentially leading to paralysis and blindness. NMO can usually be distinguished from multiple sclerosis (MS) on the basis of seropositivity for IgG antibodies against the astrocytic water channel aquaporin-4 (AQP4). Differentiation from MS is crucial, because some MS treatments can exacerbate NMO. NMO pathogenesis involves AQP4-IgG antibody binding to astrocytic AQP4, which causes complement-dependent cytotoxicity and secondary inflammation with granulocyte and macrophage infiltration, blood-brain barrier disruption and oligodendrocyte injury. Current NMO treatments include general immunosuppressive agents, B-cell depletion, and plasma exchange. Therapeutic strategies targeting complement proteins, the IL-6 receptor, neutrophils, eosinophils and CD19--all initially developed for other indications--are under clinical evaluation for repurposing for NMO. Therapies in the preclinical phase include AQP4-blocking antibodies and AQP4-IgG enzymatic inactivation. Additional, albeit currently theoretical, treatment options include reduction of AQP4 expression, disruption of AQP4 orthogonal arrays, enhancement of complement inhibitor expression, restoration of the blood-brain barrier, and induction of immune tolerance. Despite the many therapeutic options in NMO, no controlled clinical trials in patients with this condition have been conducted to date

Region-specific blood-brain barrier transporter changes leads to increased sensitivity to amisulpride in Alzheimer's disease

BACKGROUND: Research into amisulpride use in Alzheimer’s disease (AD) implicates blood–brain barrier (BBB) dysfunction in antipsychotic sensitivity. Research into BBB transporters has been mainly directed towards the ABC superfamily, however, solute carrier (SLC) function in AD has not been widely studied. This study tests the hypothesis that transporters for organic cations contribute to the BBB delivery of the antipsychotics (amisulpride and haloperidol) and is disrupted in AD. METHODS: The accumulation of [3H]amisulpride (3.7–7.7 nM) and [3H]haloperidol (10 nM) in human (hCMEC/D3) and mouse (bEnd.3) brain endothelial cell lines was explored. Computational approaches examined molecular level interactions of both drugs with the SLC transporters [organic cation transporter 1 (OCT1), plasma membrane monoamine transporter (PMAT) and multi-drug and toxic compound extrusion proteins (MATE1)] and amisulpride with the ABC transporter (P-glycoprotein). The distribution of [3H]amisulpride in wildtype and 3×transgenic AD mice was examined using in situ brain perfusion experiments. Western blots determined transporter expression in mouse and human brain capillaries . RESULTS: In vitro BBB and in silico transporter studies indicated that [3H]amisulpride and [3H]haloperidol were transported by the influx transporter, OCT1, and efflux transporters MATE1 and PMAT. Amisulpride did not have a strong interaction with OCTN1, OCTN2, P-gp, BCRP or MRP and could not be described as a substrate for these transporters. Amisulpride brain uptake was increased in AD mice compared to wildtype mice, but vascular space was unaffected. There were no measurable changes in the expression of MATE1, MATE2, PMAT OCT1, OCT2, OCT3, OCTN1, OCTN2 and P-gp in capillaries isolated from whole brain homogenates from the AD mice compared to wildtype mice. Although, PMAT and MATE1 expression was reduced in capillaries obtained from specific human brain regions (i.e. putamen and caudate) from AD cases (Braak stage V–VI) compared to age matched controls (Braak stage 0–II). CONCLUSIONS: Together our research indicates that the increased sensitivity of individuals with Alzheimer’s to amisulpride is related to previously unreported changes in function and expression of SLC transporters at the BBB (in particular PMAT and MATE1). Dose adjustments may be required for drugs that are substrates of these transporters when prescribing for individuals with AD

Operation and performance of the ATLAS Tile Calorimeter in Run 1

The Tile Calorimeter is the hadron calorimeter covering the central region of the ATLAS experiment at the Large Hadron Collider. Approximately 10,000 photomultipliers collect light from scintillating tiles acting as the active material sandwiched between slabs of steel absorber. This paper gives an overview of the calorimeter’s performance during the years 2008–2012 using cosmic-ray muon events and proton–proton collision data at centre-of-mass energies of 7 and 8TeV with a total integrated luminosity of nearly 30 fb−1. The signal reconstruction methods, calibration systems as well as the detector operation status are presented. The energy and time calibration methods performed excellently, resulting in good stability of the calorimeter response under varying conditions during the LHC Run 1. Finally, the Tile Calorimeter response to isolated muons and hadrons as well as to jets from proton–proton collisions is presented. The results demonstrate excellent performance in accord with specifications mentioned in the Technical Design Report

Search for single production of vector-like quarks decaying into Wb in pp collisions at √s = 8 TeV with the ATLAS detector

A search for singly produced vector-like Q quarks, where Q can be either a T quark with charge +2/3 or a Y quark with charge −4/3, is performed in proton–proton collisions recorded with the ATLAS detector at the LHC. The dataset corresponds to an integrated luminosity of 20.3 fb −1 and was produced with a centre-of-mass energy of √s = 8 TeV. This analysis targets Q→Wb decays where the W boson decays leptonically. A veto on massive large-radius jets is used to reject the dominant tt̄ background. The reconstructed Q-candidate mass, ranging from 0.4 to 1.2 TeV, is used in the search to discriminate signal from background processes. No significant deviation from the Standard Model expectation is observed, and limits are set on the Q→Wb cross-section times branching ratio. The results are also interpreted as limits on the QWb coupling and the mixing with the Standard Model sector for a singlet T quark or a Y quark from a doublet. T quarks with masses below 0.95 TeV are excluded at 95 % confidence level, assuming a unit coupling and a BR(T→Wb)=0.5, whereas the expected limit is 1.10 TeV

Copper Chaperone for Cu/Zn Superoxide Dismutase is a sensitive biomarker of mild copper deficiency induced by moderately high intakes of zinc

BACKGROUND: Small increases in zinc (Zn) consumption above recommended amounts have been shown to reduce copper (Cu) status in experimental animals and humans. Recently, we have reported that copper chaperone for Cu/Zn superoxide dismutase (CCS) protein level is increased in tissues of overtly Cu-deficient rats and proposed CCS as a novel biomarker of Cu status. METHODS: Weanling male Wistar rats were fed one of four diets normal in Cu and containing normal (30 mg Zn/kg diet) or moderately high (60, 120 or 240 mg Zn/kg diet) amounts of Zn for 5 weeks. To begin to examine the clinical relevance of CCS, we compared the sensitivity of CCS to mild Cu deficiency, induced by moderately high intakes of Zn, with conventional indices of Cu status. RESULTS: Liver and erythrocyte CCS expression was significantly (P < 0.05) increased in rats fed the Zn-60 and/or Zn-120 diet compared to rats fed normal levels of Zn (Zn-30). Erythrocyte CCS expression was the most sensitive measure of reduced Cu status and was able to detect a decrease in Cu nutriture in rats fed only twice the recommended amount of Zn. Liver, erythrocyte and white blood cell CCS expression showed a significant (P < 0.05) inverse correlation with plasma and liver Cu concentrations and caeruloplasmin activity. Unexpectedly, rats fed the highest level of Zn (Zn-240) showed overall better Cu status than rats fed a lower level of elevated Zn (Zn-120). Improved Cu status in these rats correlated with increased duodenal mRNA expression of several Zn-trafficking proteins (i.e. MT-1, ZnT-1, ZnT-2 and ZnT-4). CONCLUSION: Collectively, these data show that CCS is a sensitive measure of Zn-induced mild Cu deficiency and demonstrate a dose-dependent biphasic response for reduced Cu status by moderately high intakes of Zn