The REDS score: a new scoring system to risk-stratify emergency department suspected sepsis: a derivation and validation study.

OBJECTIVE: To derive and validate a new clinical prediction rule to risk-stratify emergency department (ED) patients admitted with suspected sepsis. DESIGN: Retrospective prognostic study of prospectively collected data. SETTING: ED. PARTICIPANTS: Patients aged ≥18 years who met two Systemic Inflammatory Response Syndrome criteria or one Red Flag sepsis criteria on arrival, received intravenous antibiotics for a suspected infection and admitted. PRIMARY OUTCOME MEASURE: In-hospital all-cause mortality. METHOD: The data were divided into derivation and validation cohorts. The simplified-Mortality in Severe Sepsis in the ED score and quick-SOFA scores, refractory hypotension and lactate were collectively termed 'component scores' and cumulatively termed the 'Risk-stratification of ED suspected Sepsis (REDS) score'. Each patient in the derivation cohort received a score (0-3) for each component score. The REDS score ranged from 0 to 12. The component scores were subject to univariate and multivariate logistic regression analyses. The receiver operator characteristic (ROC) curves for the REDS and the components scores were constructed and their cut-off points identified. Scores above the cut-off points were deemed high-risk. The area under the ROC (AUROC) curves and sensitivity for mortality of the high-risk category of the REDS score and component scores were compared. The REDS score was internally validated. RESULTS: 2115 patients of whom 282 (13.3%) died in hospital. Derivation cohort: 1078 patients with 140 deaths (13%). The AUROC curve with 95% CI, cut-off point and sensitivity for mortality (95% CI) of the high-risk category of the REDS score were: derivation: 0.78 (0.75 to 0.80); ≥3; 85.0 (78 to 90.5). VALIDATION: 0.74 (0.71 to 0.76); ≥3; 84.5 (77.5 to 90.0). The AUROC curve and the sensitivity for mortality of the REDS score was better than that of the component scores. Specificity and mortality rates for REDS scores of ≥3, ≥5 and ≥7 were 54.8%, 88.8% and 96.9% and 21.8%, 36.0% and 49.1%, respectively. CONCLUSION: The REDS score is a simple and objective score to risk-stratify ED patients with suspected sepsis

Lipid levels in HIV-positive men receiving anti-retroviral therapy are not associated with copy number variation of reverse cholesterol transport pathway genes Genetics

Background: The exacerbation of HIV-1 associated dyslipidemia seen in a subset of patients receiving anti-retroviral therapy suggests that genetic factors put these individuals at greater risk of cardiovascular disease. Single nucleotide polymorphisms (SNPs) within genes of and influencing the reverse cholesterol transport (RCT) pathway are associated with lipid levels but little is known regarding their copy number variation (CNV). This form of quantitative genetic variation has the potential to alter the amount of gene product made, thereby also influencing lipid metabolism. Results: To examine if CNV in RCT pathway genes was associated with altered serum lipid profiles in HIV-positive individuals receiving therapy, we designed a custom multiplex ligation-dependent probe amplification assay to screen 16 RCT genes within a subset of individuals from the Multicenter AIDS Cohort Study who show extreme lipid phenotypes. Verification of CNV was performed using a custom NanoString assay, and the Illumina HT-12 mRNA expression microarray was used to determine the influence of copy number on gene expression. Among the RCT genes, CNV was observed to be extremely rare. The only CNV seen was in the CETP gene, which showed a loss of copy in 1 of the 320 samples (0.3 %) in our study. The genes in our study showed little variation in expression between individuals, and the variation seen was not related to any detected CNV. Conclusions: Whole gene CNV is uncommon in RCT pathway genes, and not a major factor in the development of highly active antiretroviral therapy (HAART) associated dyslipidemia

One-dimensional modeling of the interaction between close-coupled injection events for a ballistic solenoid injector

This is the author s version of a work that was accepted for publication in International Journal of Engine Research. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published as https://doi.org/10.1177/1468087418760973[EN] In this article, an investigation of a solenoid common-rail injector has been carried out to understand the hydraulic interactions between close-coupled injection events. For this purpose, a one-dimensional model of the injector was developed on GT-SUITE software. The geometrical and hydraulic characteristics of the internal elements of the injector, needed to construct the model, were obtained by means of different custom-made experimental tools. The dynamic behavior of the injector was characterized using an EVI rate of injection meter. The hydraulic results from the model show a good alignment with the experiments for single injections and a varied degree of success for multiple injections. Once the model was validated, it has been used to understand the injector performance under multiple-injection strategies. The mass of a second injection has shown to highly depend on the electrical dwell time, especially at low values, mostly due to the dynamic pressure behavior in the needle seat. The critical dwell time, defined as the minimum electrical dwell time needed to obtain two independent injection events, has been numerically obtained on a wide range of operating conditions and correlated to injection pressure and energizing time of the first injection. Finally, the increase in the needle opening velocity of the second injection compared to the single-injection case has been analyzed for close-coupled injection events.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors would like to thank Jaguar Land Rover Limited for sponsoring this work.Payri, R.; De La Morena, J.; Pagano, V.; Hussain, A.; Sammut, G.; Smith, L. (2019). One-dimensional modeling of the interaction between close-coupled injection events for a ballistic solenoid injector. International Journal of Engine Research. 20(4):452-469. https://doi.org/10.1177/1468087418760973S452469204Khalek, I. A., Blanks, M. G., Merritt, P. M., & Zielinska, B. (2015). Regulated and unregulated emissions from modern 2010 emissions-compliant heavy-duty on-highway diesel engines. Journal of the Air & Waste Management Association, 65(8), 987-1001. doi:10.1080/10962247.2015.1051606Kim, H. J., Park, S. H., & Lee, C. S. (2016). Impact of fuel spray angles and injection timing on the combustion and emission characteristics of a high-speed diesel engine. Energy, 107, 572-579. doi:10.1016/j.energy.2016.04.035Mohan, B., Yang, W., & Chou, S. kiang. (2013). Fuel injection strategies for performance improvement and emissions reduction in compression ignition engines—A review. Renewable and Sustainable Energy Reviews, 28, 664-676. doi:10.1016/j.rser.2013.08.051Payri, R., Salvador, F. J., Gimeno, J., & de la Morena, J. (2009). Effects of nozzle geometry on direct injection diesel engine combustion process. Applied Thermal Engineering, 29(10), 2051-2060. doi:10.1016/j.applthermaleng.2008.10.009Payri, R., Viera, J. P., Gopalakrishnan, V., & Szymkowicz, P. G. (2016). The effect of nozzle geometry over internal flow and spray formation for three different fuels. Fuel, 183, 20-33. doi:10.1016/j.fuel.2016.06.041Hulkkonen, T., Sarjovaara, T., Kaario, O., Hamalainen, I., & Larmi, M. (2015). EXPERIMENTAL STUDY OF CONICAL DIESEL NOZZLE ORIFICE GEOMETRY. Atomization and Sprays, 25(6), 519-538. doi:10.1615/atomizspr.2015010383Kuti, O. A., Zhu, J., Nishida, K., Wang, X., & Huang, Z. (2013). Characterization of spray and combustion processes of biodiesel fuel injected by diesel engine common rail system. Fuel, 104, 838-846. doi:10.1016/j.fuel.2012.05.014Pickett, L. M., & Siebers, D. L. (2004). Soot in diesel fuel jets: effects of ambient temperature, ambient density, and injection pressure. Combustion and Flame, 138(1-2), 114-135. doi:10.1016/j.combustflame.2004.04.006Wang, X., Huang, Z., Zhang, W., Kuti, O. A., & Nishida, K. (2011). Effects of ultra-high injection pressure and micro-hole nozzle on flame structure and soot formation of impinging diesel spray. Applied Energy, 88(5), 1620-1628. doi:10.1016/j.apenergy.2010.11.035Agarwal, A. K., Dhar, A., Gupta, J. G., Kim, W. I., Choi, K., Lee, C. S., & Park, S. (2015). Effect of fuel injection pressure and injection timing of Karanja biodiesel blends on fuel spray, engine performance, emissions and combustion characteristics. Energy Conversion and Management, 91, 302-314. doi:10.1016/j.enconman.2014.12.004Zhuang, J., Qiao, X., Bai, J., & Hu, Z. (2014). Effect of injection-strategy on combustion, performance and emission characteristics in a DI-diesel engine fueled with diesel from direct coal liquefaction. Fuel, 121, 141-148. doi:10.1016/j.fuel.2013.12.032Park, S. H., Yoon, S. H., & Lee, C. S. (2011). Effects of multiple-injection strategies on overall spray behavior, combustion, and emissions reduction characteristics of biodiesel fuel. Applied Energy, 88(1), 88-98. doi:10.1016/j.apenergy.2010.07.024Mancaruso, E., Sequino, L., & Vaglieco, B. M. (2016). Analysis of the pilot injection running Common Rail strategies in a research diesel engine by means of infrared diagnostics and 1d model. Fuel, 178, 188-201. doi:10.1016/j.fuel.2016.03.066O’Connor, J., & Musculus, M. (2013). Post Injections for Soot Reduction in Diesel Engines: A Review of Current Understanding. SAE International Journal of Engines, 6(1), 400-421. doi:10.4271/2013-01-0917Bosch, W. (1966). The Fuel Rate Indicator: A New Measuring Instrument For Display of the Characteristics of Individual Injection. SAE Technical Paper Series. doi:10.4271/660749Payri, R., Salvador, F. J., Gimeno, J., & Bracho, G. (2008). A NEW METHODOLOGY FOR CORRECTING THE SIGNAL CUMULATIVE PHENOMENON ON INJECTION RATE MEASUREMENTS. Experimental Techniques, 32(1), 46-49. doi:10.1111/j.1747-1567.2007.00188.

MRAP deficiency impairs adrenal progenitor cell differentiation and gland zonation.

Melanocortin 2 receptor accessory protein (MRAP) is a single transmembrane domain accessory protein and a critical component of the hypothamo-pituitary-adrenal axis. MRAP is highly expressed in the adrenal gland and is essential for adrenocorticotropin hormone (ACTH) receptor expression and function. Human loss-of-function mutations in MRAP cause familial glucocorticoid (GC) deficiency (FGD) type 2 (FGD2), whereby the adrenal gland fails to respond to ACTH and to produce cortisol. In this study, we generated Mrap-null mice to study the function of MRAP in vivo. We found that the vast majority of Mrap-/- mice died at birth but could be rescued by administration of corticosterone to pregnant dams. Surviving Mrap-/- mice developed isolated GC deficiency with normal mineralocorticoid and catecholamine production, recapitulating FGD2. The adrenal glands of adult Mrap-/- mice were small, with grossly impaired adrenal capsular morphology and cortex zonation. Progenitor cell differentiation was significantly impaired, with dysregulation of WNT4/β-catenin and sonic hedgehog pathways. These data demonstrate the roles of MRAP in both steroidogenesis and the regulation of adrenal cortex zonation. This is the first mouse model of isolated GC deficiency and reveals the role of MRAP in adrenal progenitor cell regulation and cortex zonation.-Novoselova, T. V., Hussain, M., King, P. J., Guasti, L., Metherell, L. A., Charalambous, M., Clark, A. J. L., Chan, L. F. MRAP deficiency impairs adrenal progenitor cell differentiation and gland zonation

Momentum-resolved resonant inelastic soft X-ray scattering (qRIXS) endstation at the ALS

A momentum resolved resonant inelastic X-ray scattering (qRIXS) experimental station with continuously rotatable spectrometers and parallel detection is designed to operate at different beamlines at synchrotron and free electron laser (FEL) facilities. This endstation, currently located at the Advanced Light Source (ALS), has five emission ports on the experimental chamber for mounting the high-throughput modular soft X-ray spectrometers (MXS) [24]. Coupled to the rotation from the supporting hexapod, the scattered X-rays from 27.5° (forward scattering) to 152.5° (backward scattering) relative to the incident photon beam can be recorded, enabling the momentum-resolved RIXS spectroscopy. The components of this endstation are described in details, and the preliminary RIXS measurements on highly oriented pyrolytic graphite (HOPG) reveal the low energy vibronic excitations from the strong electron-phonon coupling at C K edge around σ* band. The grating upgrade option to enhance the performance at low photon energies is presented and the potential of this spectroscopy is discussed in summary

Symmetry breaking orbital anisotropy on detwinned Ba(Fe1-xCox)2As2 above the spin density wave transition

Nematicity, defined as broken rotational symmetry, has recently been observed in competing phases proximate to the superconducting phase in the cuprate high temperature superconductors. Similarly, the new iron-based high temperature superconductors exhibit a tetragonal to orthorhombic structural transition (i.e. a broken C4 symmetry) that either precedes or is coincident with a collinear spin density wave (SDW) transition in undoped parent compounds, and superconductivity arises when both transitions are suppressed via doping. Evidence for strong in-plane anisotropy in the SDW state in this family of compounds has been reported by neutron scattering, scanning tunneling microscopy, and transport measurements. Here we present an angle resolved photoemission spectroscopy study of detwinned single crystals of a representative family of electron-doped iron-arsenide superconductors, Ba(Fe1-xCox)2As2 in the underdoped region. The crystals were detwinned via application of in-plane uniaxial stress, enabling measurements of single domain electronic structure in the orthorhombic state. At low temperatures, our results clearly demonstrate an in-plane electronic anisotropy characterized by a large energy splitting of two orthogonal bands with dominant dxz and dyz character, which is consistent with anisotropy observed by other probes. For compositions x>0, for which the structural transition (TS) precedes the magnetic transition (TSDW), an anisotropic splitting is observed to develop above TSDW, indicating that it is specifically associated with TS. For unstressed crystals, the band splitting is observed close to TS, whereas for stressed crystals the splitting is observed to considerably higher temperatures, revealing the presence of a surprisingly large in-plane nematic susceptibility in the electronic structure.Comment: final version published in PNAS, including supplementary informatio

Reduction in BACE1 decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice

Insulin resistance and impaired glucose homoeostasis are important indicators of Type 2 diabetes and are early risk factors of AD (Alzheimer's disease). An essential feature of AD pathology is the presence of BACE1 (β-site amyloid precursor protein-cleaving enzyme 1), which regulates production of toxic amyloid peptides. However, whether BACE1 also plays a role in glucose homoeostasis is presently unknown. We have used transgenic mice to analyse the effects of loss of BACE1 on body weight, and lipid and glucose homoeostasis. BACE1−/− mice are lean, with decreased adiposity, higher energy expenditure, and improved glucose disposal and peripheral insulin sensitivity than wild-type littermates. BACE1−/− mice are also protected from diet-induced obesity. BACE1-deficient skeletal muscle and liver exhibit improved insulin sensitivity. In a skeletal muscle cell line, BACE1 inhibition increased glucose uptake and enhanced insulin sensitivity. The loss of BACE1 is associated with increased levels of UCP1 (uncoupling protein 1) in BAT (brown adipose tissue) and UCP2 and UCP3 mRNA in skeletal muscle, indicative of increased uncoupled respiration and metabolic inefficiency. Thus BACE1 levels may play a critical role in glucose and lipid homoeostasis in conditions of chronic nutrient excess. Therefore strategies that ameliorate BACE1 activity may be important novel approaches for the treatment of diabetes

On the Deformation of a Hyperelastic Tube Due to Steady Viscous Flow Within

In this chapter, we analyze the steady-state microscale fluid--structure interaction (FSI) between a generalized Newtonian fluid and a hyperelastic tube. Physiological flows, especially in hemodynamics, serve as primary examples of such FSI phenomena. The small scale of the physical system renders the flow field, under the power-law rheological model, amenable to a closed-form solution using the lubrication approximation. On the other hand, negligible shear stresses on the walls of a long vessel allow the structure to be treated as a pressure vessel. The constitutive equation for the microtube is prescribed via the strain energy functional for an incompressible, isotropic Mooney--Rivlin material. We employ both the thin- and thick-walled formulations of the pressure vessel theory, and derive the static relation between the pressure load and the deformation of the structure. We harness the latter to determine the flow rate--pressure drop relationship for non-Newtonian flow in thin- and thick-walled soft hyperelastic microtubes. Through illustrative examples, we discuss how a hyperelastic tube supports the same pressure load as a linearly elastic tube with smaller deformation, thus requiring a higher pressure drop across itself to maintain a fixed flow rate.Comment: 19 pages, 3 figures, Springer book class; v2: minor revisions, final form of invited contribution to the Springer volume entitled "Dynamical Processes in Generalized Continua and Structures" (in honour of Academician D.I. Indeitsev), eds. H. Altenbach, A. Belyaev, V. A. Eremeyev, A. Krivtsov and A. V. Porubo

Treatment variables associated with outcome in emergency department patients with suspected sepsis.

BACKGROUND: Early treatment is advocated in the management of patients with suspected sepsis in the emergency department (ED). We sought to understand the association between the ED treatments and outcome in patients admitted with suspected sepsis. The treatments studied were: (i) the time to antibiotics, where time zero is the time the patient was booked in which is also the triage time; (ii) the volume of intravenous fluid (IVF); (iii) mean arterial pressure (MAP) after 2000 ml of IVF and (iv) the final MAP in the ED. METHODS: We performed a retrospective analysis of the ED database of patients aged ≥ 18 year who met two SIRS criteria or one red flag sepsis criteria on arrival, received intravenous antibiotics for a suspected infection and admitted between 8th February 2016 and 31st August 2017. The primary outcome measure was all-cause in-hospital mortality. The four treatments stated above were controlled for severity of illness and subject to multivariate logistic regression and Cox proportional-hazard regression to identify independent predictors of mortality. RESULTS: Of the 2,066 patients studied 272 (13.2%) died in hospital. The median time to antibiotics was 48 (interquartile range 30-82) minutes. The time to antibiotics was an independent predictor of mortality only in those who developed refractory hypotension (RH); antibiotics administered more than 55 mins after arrival was associated with an odds ratio (OR) for mortality of 2.75 [95% confidence interval (CI) 1.22-6.14]. The number-needed-to-treat was 4. IVF > 2000 ml (95% CI > 500- > 2100), except in RH, and a MAP ≤ 66 mmHg after 2000 ml of IVF were also independent predictors of mortality. The OR for mortality of IVF > 2,000 ml in non-RH was 1.80 (95% CI 1.15-2.82); Number-needed-to-harm was 14. The OR for morality for a MAP ≤ 66 mmHg after 2000 ml of IVF was 3.42 (95% CI 2.10-5.57). A final MAP  2000 ml (except in RH) and a MAP ≤ 66 mmHg after 2000 ml of IVF were also independent predictors of mortality