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Supplier of system components face the challenge of customer requirements influencing the property level functional integral product architectures. For this, solution approaches focusing on the re-use of pre-engineered part variants are not applicable. However, to generate a valid product structure, customer-specific properties have to fit modelled product knowledge. Therefore, the approach models a reference class structure and analysis compatibilities on the property level for customer specific inputs concerning explicit product knowledge and constraints.
Registry-based trials have emerged as a potentially cost-saving study methodology. Early estimates of cost savings, however, conflated the benefits associated with registry utilisation and those associated with other aspects of pragmatic trial designs, which might not all be as broadly applicable. In this study, we sought to build a practical tool that investigators could use across disciplines to estimate the ranges of potential cost differences associated with implementing registry-based trials versus standard clinical trials.
We built simulation Markov models to compare unique costs associated with data acquisition, cleaning, and linkage under a registry-based trial design versus a standard clinical trial. We conducted one-way, two-way, and probabilistic sensitivity analyses, varying study characteristics over broad ranges, to determine thresholds at which investigators might optimally select each trial design.
Registry-based trials were more cost effective than standard clinical trials 98.6% of the time. Data-related cost savings ranged from $4300 to $600,000 with variation in study characteristics. Cost differences were most reactive to the number of patients in a study, the number of data elements per patient available in a registry, and the speed with which research coordinators could manually abstract data. Registry incorporation resulted in cost savings when as few as 3768 independent data elements were available and when manual data abstraction took as little as 3.4 seconds per data field.
Registries offer important resources for investigators. When available, their broad incorporation may help the scientific community reduce the costs of clinical investigation. We offer here a practical tool for investigators to assess potential costs savings.
We investigated the contribution of polymorphisms shown to moderate transcription of serotonin transporter (5HTT) and monoamine oxidase A (MAOA) to the development of violence, and furthermore to test for gene x environment interactions. To do so, a cohort of 184 adult male volunteers referred for forensic assessment were assigned to a violent or non-violent group. 45% of violent, but only 30% of non-violent individuals carried the low-activity, short MAOA allele. In the violent group, carriers of low-function variants of 5HTT were found in 77%, as compared to 59%. Logistic regression was performed and the best fitting model revealed a significant, independent effect of childhood environment and MAOA genotype. A significant influence of an interaction between childhood environment and 5HTT genotype was found (Fig. 1). MAOA thus appears to be independently associated with violent crime, while there is a relevant 5HTT x environment interaction.
The Murchison Widefield Array (MWA) is an open access telescope dedicated to studying the low-frequency (80–300 MHz) southern sky. Since beginning operations in mid-2013, the MWA has opened a new observational window in the southern hemisphere enabling many science areas. The driving science objectives of the original design were to observe 21 cm radiation from the Epoch of Reionisation (EoR), explore the radio time domain, perform Galactic and extragalactic surveys, and monitor solar, heliospheric, and ionospheric phenomena. All together
programs recorded 20 000 h producing 146 papers to date. In 2016, the telescope underwent a major upgrade resulting in alternating compact and extended configurations. Other upgrades, including digital back-ends and a rapid-response triggering system, have been developed since the original array was commissioned. In this paper, we review the major results from the prior operation of the MWA and then discuss the new science paths enabled by the improved capabilities. We group these science opportunities by the four original science themes but also include ideas for directions outside these categories.
The science of studying diamond inclusions for understanding Earth history has developed significantly over the past decades, with new instrumentation and techniques applied to diamond sample archives revealing the stories contained within diamond inclusions. This chapter reviews what diamonds can tell us about the deep carbon cycle over the course of Earth’s history. It reviews how the geochemistry of diamonds and their inclusions inform us about the deep carbon cycle, the origin of the diamonds in Earth’s mantle, and the evolution of diamonds through time.
Recent years have seen an exponential increase in the variety of healthcare data captured across numerous sources. However, mechanisms to leverage these data sources to support scientific investigation have remained limited. In 2013 the Pediatric Heart Network (PHN), funded by the National Heart, Lung, and Blood Institute, developed the Integrated CARdiac Data and Outcomes (iCARD) Collaborative with the goals of leveraging available data sources to aid in efficiently planning and conducting PHN studies; supporting integration of PHN data with other sources to foster novel research otherwise not possible; and mentoring young investigators in these areas. This review describes lessons learned through the development of iCARD, initial efforts and scientific output, challenges, and future directions. This information can aid in the use and optimisation of data integration methodologies across other research networks and organisations.
Tribology—the study of contacting, sliding surfaces—seeks to explain the fundamental mechanisms underlying friction, adhesion, lubrication, and wear, and to apply this knowledge to technologies ranging from transportation and manufacturing to biomedicine and energy. Investigating the contact and sliding of materials is complicated by the fact that the interface is buried from view, inaccessible to conventional experimental tools. In situ investigations are thus critical in visualizing and identifying the underlying physical processes. This article presents key recent advances in the understanding of tribological phenomena made possible by in situ experiments at the nanoscale. Specifically, progress in three key areas is highlighted: (1) direct observation of physical processes in the sliding contact; (2) quantitative analysis of the synergistic action of sliding and chemical reactions (known as tribochemistry) that drives material removal; and (3) understanding the surface and subsurface deformations occurring during sliding of metals. The article also outlines emerging areas where in situ nanoscale investigations can answer critical tribological questions in the future.
The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)–pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D–pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P<0·0001) and 1·8 ml (95 % CI 1·1, 2·5; P<0·0001) in AA (Prace difference=0·06), and forced vital capacity (FVC) was higher by 1·3 ml in EA (95 % CI 1·0, 1·6; P<0·0001) and 1·5 ml (95 % CI 0·8, 2·3; P=0·0001) in AA (Prace difference=0·56). Among EA, the 25(OH)D–FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1·7 ml (95 % CI 1·1, 2·3) for current smokers and 1·7 ml (95 % CI 1·2, 2·1) for former smokers, compared with 0·8 ml (95 % CI 0·4, 1·2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.
Measurements in the infrared wavelength domain allow direct assessment of the physical state and energy balance of cool matter in space, enabling the detailed study of the processes that govern the formation and evolution of stars and planetary systems in galaxies over cosmic time. Previous infrared missions revealed a great deal about the obscured Universe, but were hampered by limited sensitivity.
SPICA takes the next step in infrared observational capability by combining a large 2.5-meter diameter telescope, cooled to below 8 K, with instruments employing ultra-sensitive detectors. A combination of passive cooling and mechanical coolers will be used to cool both the telescope and the instruments. With mechanical coolers the mission lifetime is not limited by the supply of cryogen. With the combination of low telescope background and instruments with state-of-the-art detectors SPICA provides a huge advance on the capabilities of previous missions.
SPICA instruments offer spectral resolving power ranging from R ~50 through 11 000 in the 17–230 μm domain and R ~28.000 spectroscopy between 12 and 18 μm. SPICA will provide efficient 30–37 μm broad band mapping, and small field spectroscopic and polarimetric imaging at 100, 200 and 350 μm. SPICA will provide infrared spectroscopy with an unprecedented sensitivity of ~5 × 10−20 W m−2 (5σ/1 h)—over two orders of magnitude improvement over what earlier missions. This exceptional performance leap, will open entirely new domains in infrared astronomy; galaxy evolution and metal production over cosmic time, dust formation and evolution from very early epochs onwards, the formation history of planetary systems.
Outpatient parenteral antimicrobial therapy (OPAT) programmes facilitate hospital discharge, but patients remain at risk of complications and consequent healthcare utilisation (HCU). Here we elucidated the incidence of and risk factors associated with HCU in OPAT patients. This was a retrospective, single-centre, case–control study of adult patients discharged on OPAT. Cases (n = 63) and controls (n = 126) were patients that did or did not utilise the healthcare system within 60 days. Characteristics associated with HCU in bivariate analysis (P ≤ 0.2) were included in a multivariable logistic regression model. Variables were retained in the final model if they were independently (P < 0.05) associated with 60-day HCU. Among all study patients, the mean age was 55 ± 16, 65% were men, and wound infection (22%) and cellulitis (14%) were common diagnoses. The cumulative incidence of 60-day unplanned HCU was 27% with a disproportionately higher incidence in the first 30 days (21%). A statin at discharge (adjusted odds ratios (aOR) 0.23, 95% confidence intervals (CIs) 0.09–0.57), number of prior admissions in past 12 months (aOR 1.48, 95% CIs 1.05–2.10), and a sepsis diagnosis (aOR 4.62, 95% CIs 1.23–17.3) were independently associated with HCU. HCU was most commonly due to non-infection related complications (44%) and worsening primary infection (31%). There are multiple risk factors for HCU in OPAT patients, and formal OPAT clinics may help to risk stratify and target the highest risk groups.
Exercise and physical training are known to affect gastrointestinal function and digestibility in horses and can lead to inaccurate estimates of nutrient and energy digestibility when markers are used. The effect of exercise on apparent nutrient digestibility and faecal recoveries of ADL and TiO2 was studied in six Welsh pony geldings subjected to either a low- (LI) or high-intensity (HI) exercise regime according to a cross-over design. Ponies performing LI exercise were walked once per day for 45 min in a horse walker (5 km/h) for 47 consecutive days. Ponies submitted to HI exercise were gradually trained for the same 47 days according a standardized protocol. Throughout the experiment, the ponies received a fixed level of feed and the daily rations consisted of 4.7 kg DM of grass hay and 0.95 kg DM of concentrate. The diet was supplemented with minerals, vitamins and TiO2 (3.0 g Ti/day). Total tract digestibility of DM, organic matter (OM), CP, crude fat, NDF, ADF, starch, sugar and energy was determined with the total faeces collection (TFC) method. In addition, DM and OM digestibility was estimated using internal ADL and the externally supplemented Ti as markers. Urine was collected on the final 2 days of each experimental period. Exercise did not affect apparent digestibility of CP, crude fat, starch and sugar. Digestibility of DM (DMD), OM (OMD), ADF and NDF tended to be lower and DE was decreased when ponies received the HI exercise regime. For all treatments combined, mean faecal recoveries of ADL and Ti were 87.8±1.7% and 99.3±1.7%, respectively. Ti was not detected in the urine, indicating that intestinal integrity was maintained with exercise. Dry matter digestibility estimated with the TFC, ADL and Ti for ponies subjected to LI exercise were 66.3%, 60.3% and 64.8%, respectively, while DMD for HI ponies were 64.2%, 60.3% and 65.2%, respectively. In conclusion, physical exercise has an influence on the GE digestibility of the feed in ponies provided with equivalent levels of feed intake. In addition, the two markers used for estimating apparent DMD and OMD indicate that externally supplemented Ti is a suitable marker to determine digestibility of nutrients in horses performing exercise unlike dietary ADL.
Experiments and large eddy simulation (LES) were performed to study the development of the Rayleigh–Taylor instability into the saturated, nonlinear regime, produced between two gases accelerated by a rarefaction wave. Single-mode two-dimensional, and single-mode three-dimensional initial perturbations were introduced on the diffuse interface between the two gases prior to acceleration. The rarefaction wave imparts a non-constant acceleration, and a time decreasing Atwood number,
are the densities of the heavy and light gas, respectively. Experiments and simulations are presented for initial Atwood numbers of
. Nominally two-dimensional (2-D) experiments (initiated with nearly 2-D perturbations) and 2-D simulations are observed to approach an intermediate-time velocity plateau that is in disagreement with the late-time velocity obtained from the incompressible model of Goncharov (Phys. Rev. Lett., vol. 88, 2002, 134502). Reacceleration from an intermediate velocity is observed for 2-D bubbles in large wavenumber,
, experiments and simulations, where
is the wavelength of the initial perturbation. At moderate Atwood numbers, the bubble and spike velocities approach larger values than those predicted by Goncharov’s model. These late-time velocity trends are predicted well by numerical simulations using the LLNL Miranda code, and by the 2009 model of Mikaelian (Phys. Fluids., vol. 21, 2009, 024103) that extends Layzer type models to variable acceleration and density. Large Atwood number experiments show a delayed roll up, and exhibit a free-fall like behaviour. Finally, experiments initiated with three-dimensional perturbations tend to agree better with models and a simulation using the LLNL Ares code initiated with an axisymmetric rather than Cartesian symmetry.
Decline in cognitive functioning precedes the first psychotic episode in the course of schizophrenia and is considered a hallmark symptom of the disorder. Given the low incidence of schizophrenia, it remains a challenge to investigate whether cognitive decline coincides with disease-related changes in brain structure, such as white matter abnormalities. The 22q11.2 deletion syndrome (22q11DS) is an appealing model in this context, as 25% of patients develop psychosis. Furthermore, we recently showed that cognitive decline also precedes the onset of psychosis in individuals with 22q11DS. Here, we investigate whether the early cognitive decline in patients with 22q11DS is associated with alterations in white matter microstructure.
We compared the fractional anisotropy (FA) of white matter in 22q11DS patients with cognitive decline [n = 16; −18.34 (15.8) VIQ percentile points over 6.80 (2.39) years] to 22q11DS patients without cognitive decline [n = 18; 17.71 (20.17) VIQ percentile points over 5.27 (2.03) years] by applying an atlas-based approach to diffusion-weighted imaging data.
FA was significantly increased (p < 0.05, FDR) in 22q11DS patients with a cognitive decline in the bilateral superior longitudinal fasciculus, the bilateral cingulum bundle, all subcomponents of the left internal capsule and the left superior frontal-occipital fasciculus as compared with 22q11DS patients without cognitive decline.
Within 22q11DS, the early cognitive decline is associated with microstructural differences in white matter. At the mean age of 17.8 years, these changes are reflected in increased FA in several tracts. We hypothesize that similar brain alterations associated with cognitive decline take place early in the trajectory of schizophrenia.
Fontan survivors have depressed cardiac index that worsens over time. Serum biomarker measurement is minimally invasive, rapid, widely available, and may be useful for serial monitoring. The purpose of this study was to identify biomarkers that correlate with lower cardiac index in Fontan patients.
Methods and results
This study was a multi-centre case series assessing the correlations between biomarkers and cardiac magnetic resonance-derived cardiac index in Fontan patients ⩾6 years of age with biochemical and haematopoietic biomarkers obtained ±12 months from cardiac magnetic resonance. Medical history and biomarker values were obtained by chart review. Spearman’s Rank correlation assessed associations between biomarker z-scores and cardiac index. Biomarkers with significant correlations had receiver operating characteristic curves and area under the curve estimated. In total, 97 cardiac magnetic resonances in 87 patients met inclusion criteria: median age at cardiac magnetic resonance was 15 (6–33) years. Significant correlations were found between cardiac index and total alkaline phosphatase (−0.26, p=0.04), estimated creatinine clearance (0.26, p=0.02), and mean corpuscular volume (−0.32, p<0.01). Area under the curve for the three individual biomarkers was 0.63–0.69. Area under the curve for the three-biomarker panel was 0.75. Comparison of cardiac index above and below the receiver operating characteristic curve-identified cut-off points revealed significant differences for each biomarker (p<0.01) and for the composite panel [median cardiac index for higher-risk group=2.17 L/minute/m2 versus lower-risk group=2.96 L/minute/m2, (p<0.01)].
Higher total alkaline phosphatase and mean corpuscular volume as well as lower estimated creatinine clearance identify Fontan patients with lower cardiac index. Using biomarkers to monitor haemodynamics and organ-specific effects warrants prospective investigation.
Theory and experiments are reported that explore the behaviour of the Rayleigh–Taylor instability initiated with a diffuse interface. Experiments are performed in which an interface between two gases of differing density is made unstable by acceleration generated by a rarefaction wave. Well-controlled, diffuse, two-dimensional and three-dimensional, single-mode perturbations are generated by oscillating the gases either side to side, or vertically for the three-dimensional perturbations. The puncturing of a diaphragm separating a vacuum tank beneath the test section generates a rarefaction wave that travels upwards and accelerates the interface downwards. This rarefaction wave generates a large, but non-constant, acceleration of the order of
is the acceleration due to gravity. Initial interface thicknesses are measured using a Rayleigh scattering diagnostic and the instability is visualized using planar laser-induced Mie scattering. Growth rates agree well with theoretical values, and with the inviscid, dynamic diffusion model of Duff et al. (Phys. Fluids, vol. 5, 1962, pp. 417–425) when diffusion thickness is accounted for, and the acceleration is weighted using inviscid Rayleigh–Taylor theory. The linear stability formulation of Chandrasekhar (Proc. Camb. Phil. Soc., vol. 51, 1955, pp. 162–178) is solved numerically with an error function diffusion profile using the Riccati method. This technique exhibits good agreement with the dynamic diffusion model of Duff et al. for small wavenumbers, but produces larger growth rates for large-wavenumber perturbations. Asymptotic analysis shows a
decay in growth rates as
for large-wavenumber perturbations.
Rayleigh–Taylor instability experiments are performed using both immiscible and miscible incompressible liquid combinations having a relatively large Atwood number of
. The liquid-filled tank is attached to a test sled that is accelerated downwards along a vertical rail system using a system of weights and pulleys producing approximately
net acceleration. The tank is backlit and images are digitally recorded using a high-speed video camera. The experiments are either initiated with forced initial perturbations or are left unforced. The forced experiments have an initial perturbation imposed by vertically oscillating the liquid-filled tank to produce Faraday waves at the interface. The unforced experiments rely on random interfacial fluctuations, resulting from background noise, to seed the instability. The main focus of this study is to determine the effects of forced initial perturbations and the effects of miscibility on the growth parameter,
. Measurements of the mixing-layer width,
, are acquired, from which
is determined. It is found that initial perturbations of the form used in this study do not affect measured
values. However, miscibility is observed to strongly affect
, resulting in a factor of two reduction in its value, a finding not previously observed in past experiments. In addition, all measured
values are found to be smaller than those obtained in previous experimental studies.