Haemostatic resuscitation in practice: a descriptive analysis of blood products administered during Operation HERRICK, Afghanistan.

INTRODUCTION: Life-threatening haemorrhage is the leading cause of potentially survivable injury in battlefield casualties. During Operation HERRICK (Afghanistan), mortality rates improved year on year due to a number of advances in trauma care, including haemostatic resuscitation. Blood transfusion practice has not previously been reported in detail during this period. METHODS: A retrospective analysis of blood transfusion at the UK role 3 medical treatment facility (MTF) at Camp Bastion between March 2006 and September 2014 was performed. Data were extracted from two sources: the UK Joint Theatre Trauma Registry (JTTR) and the newly established Deployed Blood Transfusion Database (DBTD). RESULTS: 3840 casualties were transfused 72 138 units of blood and blood products. 2709 adult casualties (71%) were fully linked with JTTR data and were transfused a total of 59 842 units. Casualties received between 1 unit and 264 units of blood product with a median of 13 units per patient. Casualties wounded by explosion required almost twice the volume of blood product transfusion as those wounded by small arms fire or in a motor vehicle collision (18 units, 9 units, and 10 units, respectively). More than half of blood products were transfused within the first 2 hours following arrival at the MTF. There was a trend towards balanced resuscitation with more equal ratios of blood and blood products being used over time. CONCLUSION: This study has defined the epidemiology of blood transfusion practice during Operation HERRICK. The DBTD is the largest combined trauma database of its kind. It will ensure that lessons learnt during this period are defined and not forgotten; it should also allow further research questions to be answered in this important area of resuscitation practice.

Contribution of local regeneration of glucocorticoids to tissue steroid pools.

11ß-Hydroxysteroid dehydrogenase 1 (11ßHSD1) is a drug target to attenuate adverse effects of chronic glucocorticoid excess. It catalyses intracellular regeneration of active glucocorticoids in tissues including brain, liver and adipose tissue (coupled to hexose-6-phosphate dehydrogenase, H6PDH). 11ßHSD1 activity in individual tissues is thought to contribute significantly to glucocorticoid levels at those sites, but its local contribution vs glucocorticoid delivery via the circulation is unknown. Here, we hypothesised that hepatic 11ßHSD1 would contribute significantly to the circulating pool. This was studied in mice with Cre-mediated disruption of Hsd11b1 in liver (Alac-Cre) vs adipose tissue (aP2-Cre) or whole-body disruption of H6pdh. Regeneration of [9,12,12-2H3]-cortisol (d3F) from [9,12,12-2H3]-cortisone (d3E), measuring 11ßHSD1 reductase activity was assessed at steady state following infusion of [9,11,12,12-2H4]-cortisol (d4F) in male mice. Concentrations of steroids in plasma and amounts in liver, adipose tissue and brain were measured using mass spectrometry interfaced with matrix-assisted laser desorption ionisation or liquid chromatography. Amounts of d3F were higher in liver, compared with brain and adipose tissue. Rates of appearance of d3F were ~6-fold slower in H6pdh-/- mice, showing the importance for whole-body 11ßHSD1 reductase activity. Disruption of liver 11ßHSD1 reduced the amounts of d3F in liver (by ~36%), without changes elsewhere. In contrast disruption of 11ßHSD1 in adipose tissue reduced rates of appearance of circulating d3F (by ~67%) and also reduced regenerated of d3F in liver and brain (both by ~30%). Thus, the contribution of hepatic 11ßHSD1 to circulating glucocorticoid levels and amounts in other tissues is less than that of adipose tissue.

A versatile microtomography system to study in situ the failure and fragmentation in geomaterials.

This article describes a microtomography experimental platform enabling in situ micro-mechanical study of failure and fragmentation in geomaterials. The system is based on an original high-pressure triaxial flow cell, which is fully integrated into a custom built microtomography scanner equipped with a laboratory x-ray source. The design of the high-precision mechanical apparatus was informed by the concurrent development of advanced tomographic reconstruction methods based on helical scanning and of algorithms correcting for hardware inaccuracies. This experimental system produces very high-quality 3D images of microstructural changes occurring in rocks undergoing mechanical failure and substantial fragmentation. We present the results of two experiments as case studies to demonstrate the capabilities and versatility of this instrumental platform. These experiments tackle various questions related to the onset of rock failure, the hydromechanical coupling and relaxation mechanisms in fractured rocks, or the fragmentation process in geomaterials such as copper ores.

Impact of mismatches in HbA1c vs glucose values on the diagnostic classification of diabetes and prediabetes.

AIMS: To determine whether HbA1c mismatches (HbA1c levels that are higher or lower than expected for the average glucose levels in different individuals) could lead to errors if diagnostic classification is based only on HbA1c levels. METHODS: In a cross-sectional study, 3106 participants without known diabetes underwent a 75-g oral glucose tolerance test (fasting glucose and 2-h glucose) and a 50-g glucose challenge test (1-h glucose) on separate days. They were classified by oral glucose tolerance test results as having: normal glucose metabolism; prediabetes; or diabetes. Predicted HbA1c was determined from the linear regression modelling the relationship between observed HbA1c and average glucose (mean of fasting glucose and 2-h glucose from the oral glucose tolerance test, and 1-h glucose from the glucose challenge test) within oral glucose tolerance test groups. The haemoglobin glycation index was calculated as [observed - predicted HbA1c ], and divided into low, intermediate and high haemoglobin glycation index mismatch tertiles. RESULTS: Those participants with higher mismatches were more likely to be black, to be men, to be older, and to have higher BMI (all P<0.001). Using oral glucose tolerance test criteria, the distribution of normal glucose metabolism, prediabetes and diabetes was similar across mismatch tertiles; however, using HbA1c criteria, the participants with low mismatches were classified as 97% normal glucose metabolism, 3% prediabetes and 0% diabetes, i.e. mostly normal, while those with high mismatches were classified as 13% normal glucose metabolism, 77% prediabetes and 10% diabetes, i.e. mostly abnormal (P<0.001). CONCLUSIONS: Measuring only HbA1c could lead to under-diagnosis in people with low mismatches and over-diagnosis in those with high mismatches. Additional oral glucose tolerance tests and/or fasting glucose testing to complement HbA1c in diagnostic classification should be performed in most individuals.

Resilient Entangling Gates for Trapped Ions.

Constructing a large-scale ion trap quantum processor will require entangling gate operations that are robust in the presence of noise and experimental imperfection. We experimentally demonstrate how a new type of Mølmer-Sørensen gate protects against infidelity caused by heating of the motional mode used during the gate. Furthermore, we show how the same technique simultaneously provides significant protection against slow fluctuations and mis-sets in the secular frequency. Since this parameter sensitivity is worsened in cases where the ions are not ground-state cooled, our method provides a path towards relaxing ion cooling requirements in practical realizations of quantum computing and simulation.

Quantification of 11ß-hydroxysteroid dehydrogenase 1 kinetics and pharmacodynamic effects of inhibitors in brain using mass spectrometry imaging and stable-isotope tracers in mice.

11ß-Hydroxysteroid dehydrogenase 1 (11ß-HSD1; EC 1.1.1.146) generates active glucocorticoid hormones. Small molecule inhibitors have been developed to target 11ß-HSD1 for the treatment of dementia; these must enter brain subregions, such as the hippocampus, to be effective. We previously reported mass spectrometry imaging measurement of murine tissue steroids, and deuterated steroid tracer infusion quantification of 11ß-HSD1 turnover in humans. Here, these tools are combined to assess tissue pharmacokinetics and pharmacodynamics of an 11ß-HSD1 inhibitor that accesses the brain. [9,11,12,12-2H]4-Cortisol was infused (1.75 mg/day) by minipump for 2 days into C57Bl6 mice (male, age 12 weeks, n = 3/group) after which an 11ß-HSD1 inhibitor (UE2316) was administered (25 mg/kg oral gavage) and animals culled immediately or 1, 2 and 4 h post-dosing. Mice with global genetic disruption of Hsd11B1 were studied similarly. Turnover of d4-cortisol to d3-cortisone (by loss of the 11-deuterium) and regeneration of d3-cortisol (by 11ß-HSD1-mediated reduction) were assessed in plasma, liver and brain using matrix assisted laser desorption ionization coupled to Fourier transform cyclotron resonance mass spectrometry. The tracer d4-cortisol was detected in liver and brain following a two day infusion. Turnover to d3-cortisone and on to d3-cortisol was slower in brain than liver. In contrast, d3-cortisol was not detected in mice lacking 11ß-HSD1. UE2316 impaired d3-cortisol generation measured in whole body (assessed in plasma; 53.1% suppression in rate of appearance in d3-cortisol), liver and brain. Differential inhibition in brain regions was observed; active glucocorticoids were suppressed to a greater in extent hippocampus or cortex than in amygdala. These data confirm that the contribution of 11ß-HSD1 to the tissue glucocorticoid pool, and the consequences of enzyme inhibition on active glucocorticoid concentrations, are substantial, including in the brain. They further demonstrate the value of mass spectrometry imaging in pharmacokinetic and pharmacodynamic studies.

The Impact of Order Source Misattribution on Computerized Provider Order Entry (CPOE) Performance Metrics.

BACKGROUND: One strategy to foster adoption of computerized provider order entry (CPOE) by physicians is the monthly distribution of a list identifying the number and use rate percentage of orders entered electronically versus on paper by each physician in the facility. Physicians care about CPOE use rate reports because they support the patient safety and quality improvement objectives of CPOE implementation. Certain physician groups are also motivated because they participate in contracted financial and performance arrangements that include incentive payments or financial penalties for meeting (or failing to meet) a specified CPOE use rate target. Misattribution of order sources can hinder accurate measurement of individual physician CPOE use and can thereby undermine providers' confidence in their reported performance, as well as their motivation to utilize CPOE. Misattribution of order sources also has significant patient safety, quality, and medicolegal implications. OBJECTIVE: This analysis sought to evaluate the magnitude and sources of misattribution among hospitalists with high CPOE use and, if misattribution was found, to formulate strategies to prevent and reduce its recurrence, thereby ensuring the integrity and credibility of individual and facility CPOE use rate reporting. METHODS: A detailed manual order source review and validation of all orders issued by one hospitalist group at a midsize community hospital was conducted for a one-month study period. RESULTS: We found that a small but not dismissible percentage of orders issued by hospitalists-up to 4.18 percent (95 percent confidence interval, 3.84-4.56 percent) per month-were attributed inaccurately. Sources of misattribution by department or function were as follows: nursing, 42 percent; pharmacy, 38 percent; laboratory, 15 percent; unit clerk, 3 percent; and radiology, 2 percent. Order management and protocol were the most common correct order sources that were incorrectly attributed. CONCLUSION: Order source misattribution can negatively affect reported provider CPOE use rates and should be investigated if providers perceive discrepancies between reported rates and their actual performance. Preventive education and communication efforts across departments can help prevent and reduce misattribution.

Clinical impact and value of workstation single sign-on.

BACKGROUND: CHRISTUS Health began implementation of computer workstation single sign-on (SSO) in 2015. SSO technology utilizes a badge reader placed at each workstation where clinicians swipe or "tap" their identification badges. OBJECTIVE: To assess the impact of SSO implementation in reducing clinician time logging in to various clinical software programs, and in financial savings from migrating to a thin client that enabled replacement of traditional hard drive computer workstations. METHODS: Following implementation of SSO, a total of 65,202 logins were sampled systematically during a 7day period among 2256 active clinical end users for time saved in 6 facilities when compared to pre-implementation. Dollar values were assigned to the time saved by 3 groups of clinical end users: physicians, nurses and ancillary service providers. RESULTS: The reduction of total clinician login time over the 7day period showed a net gain of 168.3h per week of clinician time - 28.1h (2.3 shifts) per facility per week. Annualized, 1461.2h of mixed physician and nursing time is liberated per facility per annum (121.8 shifts of 12h per year). The annual dollar cost savings of this reduction of time expended logging in is $92,146 per hospital per annum and $1,658,745 per annum in the first phase implementation of 18 hospitals. Computer hardware equipment savings due to desktop virtualization increases annual savings to $2,333,745. Qualitative value contributions to clinician satisfaction, reduction in staff turnover, facilitation of adoption of EHR applications, and other benefits of SSO are discussed. CONCLUSIONS: SSO had a positive impact on clinician efficiency and productivity in the 6 hospitals evaluated, and is an effective and cost-effective method to liberate clinician time from repetitive and time consuming logins to clinical software applications.

Trapped-Ion Quantum Logic with Global Radiation Fields.

Trapped ions are a promising tool for building a large-scale quantum computer. However, the number of required radiation fields for the realization of quantum gates in any proposed ion-based architecture scales with the number of ions within the quantum computer, posing a major obstacle when imagining a device with millions of ions. Here, we present a fundamentally different approach for trapped-ion quantum computing where this detrimental scaling vanishes. The method is based on individually controlled voltages applied to each logic gate location to facilitate the actual gate operation analogous to a traditional transistor architecture within a classical computer processor. To demonstrate the key principle of this approach we implement a versatile quantum gate method based on long-wavelength radiation and use this method to generate a maximally entangled state of two quantum engineered clock qubits with fidelity 0.985(12). This quantum gate also constitutes a simple-to-implement tool for quantum metrology, sensing, and simulation.

Tackling the burden of the hepatitis C virus in the UK: characterizing and assessing the clinical and economic consequences.

OBJECTIVES: The hepatitis C virus (HCV) remains a significant public health issue. This study aimed to quantify the clinical and economic burden of chronic hepatitis C in the UK, stratified by disease severity, age and awareness of infection, with concurrent assessment of the impact of implementing a treatment prioritization approach. STUDY DESIGN AND METHODS: A previously published back projection, natural history and cost-effectiveness HCV model was adapted to a UK setting to estimate the disease burden of chronic hepatitis C and end-stage liver disease (ESLD) between 1980 and 2035. A published meta-regression analysis informed disease progression, and UK-specific data informed other model inputs. RESULTS: At 2015, prevalence of chronic hepatitis C is estimated to be 241,487 with 22.20%, 33.72%, 17.22%, 16.67% and 10.19% of patients in METAVIR stages F0, F1, F2, F3 and F4, respectively, but is estimated to fall to 193,999 by 2035. ESLD incidence is predicted to peak in 2031. Assuming all patients are diagnosed and treatment is prioritized in F3 and F4 using highly efficacious direct-acting antiviral (DAA) regimens, a 69.85% reduction in ESLD incidence is predicted between 2015 and 2035, and the cumulative discounted medical expenditure associated with the lifetime management of incident ESLD events is estimated to be £1,202,827,444. CONCLUSIONS: The prevalence of chronic hepatitis C is expected to fall in coming decades; however, the ongoing financial burden is expected to be high due to an increase in ESLD incidence. This study highlights the significant costs of managing ESLD that are likely to be incurred without the employment of effective treatment approaches.

Overexpression of human kynurenine-3-monooxygenase protects against 3-hydroxykynurenine-mediated apoptosis through bidirectional nonlinear feedback.

Kynurenine 3-monooxygenase (KMO) is a critical regulator of inflammation. The preferred KMO substrate, kynurenine, is converted to 3-hydroxykynurenine (3HK), and this product exhibits cytotoxicity through mechanisms that culminate in apoptosis. Here, we report that overexpression of human KMO with orthotopic localisation to mitochondria creates a metabolic environment during which the cell exhibits increased tolerance for exogenous 3HK-mediated cellular injury. Using the selective KMO inhibitor Ro61-8048, we show that KMO enzyme function is essential for cellular protection. Pan-caspase inhibition with Z-VAD-FMK confirmed apoptosis as the mode of cell death. By defining expression of pathway components upstream and downstream of KMO, we observed alterations in other key kynurenine pathway components, particularly tryptophan-2,3-dioxygenase upregulation, through bidirectional nonlinear feedback. KMO overexpression also increased expression of inducible nitric oxide synthase (iNOS). These changes in gene expression are functionally relevant, because siRNA knockdown of the pathway components kynureninase and quinolinate phosphoribosyl transferase caused cells to revert to a state of susceptibility to 3HK-mediated apoptosis. In summary, KMO overexpression, and importantly KMO activity, have metabolic repercussions that fundamentally affect resistance to cell stress.

Toward the Elimination of Paper Orders: Managing the Challenge of Low Frequency Physician Users of Computerized Patient Order Entry (CPOE).

With the adoption of Computerized Patient Order Entry (CPOE), many physicians - particularly consultants and those who are affiliated with multiple hospital systems - are faced with the challenge of learning to navigate and commit to memory the details of multiple EHRs and CPOE software modules. These physicians may resist CPOE adoption, and their refusal to use CPOE presents a risk to patient safety when paper and electronic orders co-exist, as paper orders generated in an electronic ordering environment can be missed or acted upon after delay, are frequently illegible, and bypass the Clinical Decision Support (CDS) that is part of the evidence-based value of CPOE. We defined a category of CPOE Low Frequency Users (LFUs) - physicians issuing a total of less than 10 orders per month - and found that 50.4% of all physicians issuing orders in 3 urban/suburban hospitals were LFUs and actively issuing orders across all shifts and days of the week. Data are presented for 2013 on the number of LFUs by month, day of week, shift and facility, over 2.3 million orders issued. A menu of 6 options to assist LFUs in the use of CPOE, from which hospital leaders could select, was instituted so that paper orders could be increasingly eliminated. The options, along with their cost implications, are described, as is the initial option selected by hospital leaders. In practice, however, a mixed pattern involving several LFU support options emerged. We review data on how the option mix selected may have impacted CPOE adoption and physician use rates at the facilities. The challenge of engaging LFU physicians in CPOE adoption may be common in moderately sized hospitals, and these options can be deployed by other systems in advancing CPOE pervasiveness of use and the eventual elimination of paper orders.

Hybrid quantum logic and a test of Bell's inequality using two different atomic isotopes.

Entanglement is one of the most fundamental properties of quantum mechanics, and is the key resource for quantum information processing (QIP). Bipartite entangled states of identical particles have been generated and studied in several experiments, and post-selected or heralded entangled states involving pairs of photons, single photons and single atoms, or different nuclei in the solid state, have also been produced. Here we use a deterministic quantum logic gate to generate a 'hybrid' entangled state of two trapped-ion qubits held in different isotopes of calcium, perform full tomography of the state produced, and make a test of Bell's inequality with non-identical atoms. We use a laser-driven two-qubit gate, whose mechanism is insensitive to the qubits' energy splittings, to produce a maximally entangled state of one (40)Ca(+) qubit and one (43)Ca(+) qubit, held 3.5 micrometres apart in the same ion trap, with 99.8 ± 0.6 per cent fidelity. We test the CHSH (Clauser-Horne-Shimony-Holt) version of Bell's inequality for this novel entangled state and find that it is violated by 15 standard deviations; in this test, we close the detection loophole but not the locality loophole. Mixed-species quantum logic is a powerful technique for the construction of a quantum computer based on trapped ions, as it allows protection of memory qubits while other qubits undergo logic operations or are used as photonic interfaces to other processing units. The entangling gate mechanism used here can also be applied to qubits stored in different atomic elements; this would allow both memory and logic gate errors caused by photon scattering to be reduced below the levels required for fault-tolerant quantum error correction, which is an essential prerequisite for general-purpose quantum computing.

Ground-State Cooling of a Trapped Ion Using Long-Wavelength Radiation.

We demonstrate ground-state cooling of a trapped ion using radio-frequency (rf) radiation. This is a powerful tool for the implementation of quantum operations, where rf or microwave radiation instead of lasers is used for motional quantum state engineering. We measure a mean phonon number of n[over ¯]=0.13(4) after sideband cooling, corresponding to a ground-state occupation probability of 88(7)%. After preparing in the vibrational ground state, we demonstrate motional state engineering by driving Rabi oscillations between the |n=0⟩ and |n=1⟩ Fock states. We also use the ability to ground-state cool to accurately measure the motional heating rate and report a reduction by almost 2 orders of magnitude compared with our previously measured result, which we attribute to carefully eliminating sources of electrical noise in the system.