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Therapeutic trials in Huntington's disease (HD) are challenging as clinical progression is slow and variable and reliable biomarkers are lacking. We used magnetic resonance imaging and the brain boundary shift integral to quantify whole-brain atrophy rates over 1 year in early and premanifest HD subjects, and controls. Early HD subjects had statistically significantly ( P = 0.007) increased (threefold higher) rates of whole-brain atrophy compared with controls. Higher atrophy rates were associated with longer CAG repeat length. MRI-based measures of whole-brain atrophy may have potential as a measure of progression in HD. © 2009 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Huntington’s disease (HD) is caused by an expanded CAG repeat on the gene encoding for the protein huntingtin. There are conflicting findings about the extent to which repeat length predicts signs of the disease or severity of disease progression in adults. This study examined the relationship between CAG repeat length and brain volume in a large cohort of pre- and post-motor onset HD gene carriers, using voxel-based morphometry (VBM), an approach which allowed us to investigate the whole brain without defining a priori regions of interest. We also used VBM to examine group differences between 20 controls, 21 premanifest, and 40 early HD subjects. In the 61 mutation-positive subjects higher CAG repeat length was significantly associated with reduced volume of the body of the caudate nucleus bilaterally, left putamen, right insula, right parahippocampal gyrus, right anterior cingulate, and right occipital lobe, after correcting for age. The group contrasts showed significant reduction in grey matter volume in the early HD group relative to controls in widespread cortical as well as subcortical areas but there was no evidence of difference between controls and premanifest subjects. Overall we have demonstrated that increased CAG repeat length is associated with atrophy in extra-striatal as well as striatal regions, which has implications for the monitoring of disease-modifying therapies in the condition. [ABSTRACT FROM AUTHOR]

Open cavities at transonic speeds can result in acoustic resonant flow behavior with fluctuating pressure levels of sufficient intensity to cause significant damage to internal stores and surrounding structures. Extensive research in this field has produced numerous cavity flow control techniques, the more effective of which may require costly feedback control systems or entail other drawbacks such as drag penalties or rapid performance degradation at off-design condition. The current study focuses on the use of simple geometric modifications of a rectangular planform cavity with the aim of attenuating the aeroacoustic signature. Experiments were performed in an intermittent suck-down transonic wind tunnel by using a typical open flow rectangular planform cavity, which was modularly designed such that the leading and trailing edge geometries could be modified by using a family of inserts. The current work focused on a variety of recessed leading edge step arrangements. Configurations were tested at transonic Mach numbers spanning the range Mach 0.7-0.9, and unsteady pressure measurements were recorded at various stations within the cavity in order to obtain acoustic spectra. The most effective configuration at Mach 0.9 was the leading edge step employing a step height to step length ratio of 0.4. This configuration achieved a tonal attenuation of up to 18.6 dB and an overall sound pressure level (OASPL) reduction of approximately 7.5 dB. This is a significant level of noise suppression in comparison with other passive control methods. In addition, it offers the additional benefits of being a simple geometric feature, which does not rely on placing flow effectors into the high-speed grazing flow. [ABSTRACT FROM AUTHOR]

There is increasing interest in imaging cadavers for noninvasive autopsies for research purposes. However, the temperature is well below that of in vivo imaging, and a variety of interesting 'cold brain' effects are observed. At lower temperatures conventional FLAIR sequences no longer produce dark cerebrospinal fluid (CSF); T1 is reduced from about 4.0 sec in vivo to 1.7 sec at 1°C. The diffusion coefficient (DC) of CSF is much reduced (from 3.1 10−9 m2s−1 in vivo to 1.1 at 1°C). DC values therefore provide a noninvasive thermometer to measure brain core temperature to within 1.0°C. In three cadavers DC values were 1.1-1.5 10−9 m2s−1, indicating brain core temperatures of 1-10°C, consistent with external thermocouple measurements. An improved inversion time (TI0) can then be found for FLAIR. At 10°C this Cold FLAIR sequence (TI0 = 1.5 sec) gave black CSF. Expressions for CSF DC and T1 as a function of temperature were produced. A measurement of CSF DC could be converted directly to temperature and the required TI0 found. In vitro values of CSF DC were about 1% lower than that of water. Thus, FLAIR imaging can be optimized for cadaveric brains at low and unknown temperatures, thereby improving value for autopsy purposes and facilitating comparisons with in vivo imaging. Magn Reson Med, 2007. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

In July 1925 Heisenberg published a paper that ushered in the new era of quantum mechanics. This epoch-making paper is generally regarded as being difficult to follow, partly because Heisenberg provided few clues as to how he arrived at his results. We give details of the calculations of the type that Heisenberg might have performed. As an example we consider one of the anharmonic oscillator problems considered by Heisenberg, and use our reconstruction of his approach to solve it up to second order in perturbation theory. The results are precisely those obtained in standard quantum mechanics, and we suggest that a discussion of the approach, which is based on the direct calculation of transition frequencies and amplitudes, could usefully be included in undergraduate courses on quantum mechanics. [ABSTRACT FROM AUTHOR]

This study reports the prospective follow–up of a cohort of patients with acute optic neuritis examined with serial visual tests, visual evoked potentials (VEPs), conventional and triple–dose gadolinium (Gd)–enhanced magnetic resonance imaging (MRI) to examine which factors are important in visual recovery. Thirty–three patients were recruited with acute unilateral optic neuritis. A clinical and VEP assessment was performed on each. Optic nerve MRI was performed using fast spin echo (FSE) (on all) and triple-dose Gdenhanced T1–weighted sequences (n = 28). Optic nerve lesion lengths were measured. Serial assessments were performed on 22 of the patients up to one–year. Serial Gd–enhanced optic nerve imaging was performed on 15 of the patients until enhancement ceased. The final 30–2 Humphrey visual field mean deviation (MD) was 2.55 dB higher in patients in the lowest quartile of initial Gd–enhanced lesion length compared with the other quartiles (p < 0.01) but recovery was not related to the duration of enhancement. The initial recovery of Humphrey MD was 4.60 dB units per day in patients with good eventual recoveries (MD > –6.0 dB) and 0.99 dB per day in poor-recovery patients (p = 0.02).Good–recovery patients had mean central field VEP amplitudes 2.29 µV higher during recovery than poor-recovery patients (p = 0.047). The results suggest that factors which are associated with a better prognosis are: having a short acute lesion on triple–dose gadolinium enhanced imaging, higher VEP amplitudes during recovery and a steep gradient of the initial improvement in vision. [ABSTRACT FROM AUTHOR]

Background:. Natalizumab, a humanized monoclonal anti-adhesion molecule antibody, reduces the frequency of new gadolinium (Gd) enhancing lesions and relapses in multiple sclerosis (MS). Its effect on evolution of new Gd enhancing lesions to T1 hypointense lesions is unknown. Methods:. 213 patients were randomized to receive 3 mg/kg or 6 mg/kg natalizumab or placebo monthly for 6 months and then followed for a further 6 months. A subset of patients who had one or more new gadolinium enhancing lesions from Month 0 to Month 6 and available electronic data were analysed. Each new Gd enhancing lesion that developed during treatment (months 1–6) was investigated for conversion to a new T1 hypointense lesion at month 12. Lesions were classified as large or small if their cross-sectional area was greater or less than 20mm2. Because of the similarity of both doses of natalizumab on the frequency of new Gd enhancing lesions, the two natalizumab arms were combined in all analyses. Results:. Compared with the placebo group, the natalizumab group exhibited significant decreases in: (i) the proportion of patients with new Gd enhancing lesions that evolved to T1-hypointense lesions (10/38 [26 %] versus 27/40 [68 %]; p < 0.01); (ii) the proportion of patients who developed large T1 hypointense lesions (2/38 [5 %] versus 16/40 [40 %]; p < 0.01); (iii) the proportion of new Gd enhancing lesions that became T1 hypointense (11/75 [15 %] versus 118/466 [25 %]; p = 0.045); (iv) the mean proportion per patient of new Gd enhancing lesions that converted to T1-hypointense lesions (0.15 versus 0.28; p = 0.005), and (v) the odds ratio (OR) of converting from Gd enhancing to T1-hypointense lesions (OR = 0.48; 95% CI = 0.24, 0.94, p = 0.031)). Conclusion:. Natalizumab significantly suppresses the evolution of new Gd enhancing to T1-hypointense lesions. This may reflect several mechanisms including reduced cell migration across the blood brain barrier, reduced T cell activation within lesions, an inhibitory effect on subsequent axonal damage within the new central nervous system lesion, and a reduced likelihood of recurrent lesion inflammation. [ABSTRACT FROM AUTHOR]

Aero-engine nacelles have to fulfill design requirements at both cruise and off-design conditions. Under engine windmilling conditions the ingested streamtube massflow is relatively low. A key off-design condition is take-off, which, in conjunction with an engine windmilling scenario, results in the stagnation point of the ingested streamtube being located significantly inside the intake. The combination of high angle of attack and low engine massflow rates leads to a strong flow acceleration and subsequent diffusion of the boundary layer on the upper quadrants of the external nacelle cowl, which can terminate with subsonic separation from the leading-edge. Under this condition, Reynolds number effects can play a dominant role on the separation onset and characteristics and 3D-annular wind tunnel tests cannot always achieve Reynolds' number equivalent to full scale. A novel quasi-2D rig configuration representative of the aerodynamics of a full-size aero-engine nacelle under windmilling end of runway conditions examined in detail the characteristics of the boundary layer on the external cowl of a nacelle prior to diffusion-induced separation. Separation of the boundary layer was independently promoted through changes to represent different engine massflow rates and freestream Mach number on the rig to determine the limits of steady Reynolds Averaged Navier Stokes (RANS) methods to discern the onset of boundary layer separation. For the conditions and geometry investigated, the combined experimental and computational results showed that there was laminar to turbulent transition of the boundary layer ahead of the subsonic diffusion. The work showed that steady RANS can predict the onset of boundary layer separation with an uncertainty of approximately 10% on notional engine massflow rate and 0.05 on freestream Mach number relative to a nominal operating freestream Mach number of 0.25. This provides guidance for the industrial design and optimization of future windmilling-tolerant nacelles for large ultra-high bypass ratio turbofan engines. • CFD validation for aero-engine nacelles under end-of-runway windmilling conditions. • Full-size engine Reynolds number representative conditions. • Laminar to turbulent transition of the nacelle boundary layer identified. • Steady RANS able to discern onset of flow separation on nacelle external cowl. • Guidance for the aerodynamic design optimisation of windmilling-tolerant nacelles. [ABSTRACT FROM AUTHOR]

A regioselective synthesis of 6′- O-acyl sucrose monoesters has been developed through the lipase-catalyzed esterification of sucrose acetals with fatty acids in both organic solvents and under solvent-free conditions. The products were obtained in overall yields of 20-27% after hydrolysis of the isopropylidene groups with aqueous acids. The strict selectivity of the enzymes used also enabled the preparation of a monoester fraction that was highly enriched in 6- O-acyl sucrose. This was accomplished by lipase-catalyzed transesterification of sucrose monoesters, prepared by conventional chemical methods, in propan-2-ol. After removal of the transesterification products (sucrose and fatty acid isopropyl esters) and column chromatography on silica gel, the obtained monoester product contained 80% of the single regioisomer, 6- O-acyl sucrose. [ABSTRACT FROM AUTHOR]

As the size of aero-engines has increased in recent years, the need for slimmer and shorter nacelles has become more pressing. A more aggressive design space must therefore be explored for nacelle designs which are expected to perform worse in the off design conditions such as spillage than current nacelle designs. In this work, a novel design space has been explored through the use of an optimisation method which evaluated nacelle aerodynamic performance based on computational fluid dynamics simulations. A multi-objective optimisation was undertaken where cruise drag, drag rise Mach number, spillage drag and two metrics based on the pressure distribution of the nacelle were optimised. Comparable optimal designs were picked from the Pareto sets of optimisations carried out at different nacelle lengths and radial offsets and some key outcomes established from their aerodynamics and geometries. It was determined that a reduction in the length of the nacelle from 3.8 highlight radii to 3.1 radii resulted in a significantly worse aerodynamic performance which included an increase in peak surface isentropic Mach number at cruise of 0.1 and up to four times as much spillage drag. It was however also established from the optimisation results that as the required drag rise Mach number was decreased the overall performance of short nacelles improved significantly. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) treatment intervention with immunomodulating therapy at early disease stage improves short term clinical outcomes. The objective of this study is to describe the long-term outcomes and healthcare utilization of patients with clinically isolated syndrome (CIS) included in the Betaferon®/Betaseron® in Newly Emerging MS for Initial Treatment (BENEFIT) randomized, parallel group trial. In BENEFIT patients were assigned to "early" IFNB-1b treatment or placebo ("delayed" treatment). After 2 years or conversion to clinically definite multiple sclerosis (CDMS), all patients were offered IFNB-1b and were reassessed 15 years later. Of 468 patients, 261 (55.8%) were enrolled into BENEFIT 15 (161 [55.1%] from the early, 100 [56.8%] from the delayed treatment arm). In the full BENEFIT analysis set, risk of conversion to CDMS remained lower in the early treatment group (– 30.5%; hazard ratio 0.695 [95% CI, 0.547–0.883]; p = 0.0029) with a 15.7% lower risk of relapse than in the delayed treatment group (p = 0.1008). Overall, 25 patients (9.6%; 9.9% early, 9.0% delayed) converted to secondary progressive multiple sclerosis. Disability remained low and stable with no significant difference between groups in Expanded Disability Status Scale score or MRI metrics. Paced Auditory Serial Addition Task-3 scores were better in the early treatment group (p = 0.0036 for treatment effect over 15 years). 66.3% of patients were still employed at Year 15 versus 74.7% at baseline. In conclusion, results 15 years from initial randomization support long-term benefits of early treatment with IFNB-1b. [ABSTRACT FROM AUTHOR]

Genetic algorithms are a powerful optimisation technique for the design of complex engineering systems. Although computing power continuously grows, methods purely based on expensive numerical simulations are still challenging for the optimisation of aerodynamic components at an early stage of the design process. For this reason, response surface models are typically employed as a driver of the genetic algorithm. This reduces considerably the total overhead computational cost but at the expense of an inherent prediction uncertainty. Aero-engine nacelle design is a complex multi-objective optimisation problem due to the nonlinearity of transonic flow aerodynamics. This research develops a new framework, that combines surrogate modelling and numerical simulations, for the multi-objective optimisation of aero-engine nacelles. The method initially employs numerical simulations to guide the genetic algorithm through generations and uses a combination of higher fidelity results along with evolving surrogate models to identify a set of optimum designs. This new approach has been applied to the multi-objective optimisation of civil aero-engines which are representative of future turbofan configurations. Compared to the conventional CFD in-the-loop optimisation method, the proposed algorithm successfully identified the same set of optimum nacelle designs at a 25% reduction in the computational cost. Within the context of preliminary design, the method meets the typical 5% acceptability criterion with a 65% reduction in computational cost. [ABSTRACT FROM AUTHOR]

It is envisaged that future civil aero-engines will operate with greater bypass ratios compared to contemporary configurations to lower specific thrust and improve propulsive efficiency. This trend is likely to be accompanied with the implementation of a shorter nacelle and bypass duct for larger engines. However, a short bypass duct may result in an aerodynamic coupling between the exit flow conditions of the fan Outlet Guide Vanes (OGVs) and the exhaust system. Thus, it is imperative that the design of the exhaust is carried out in combination with the fan exit profile. A parabolic definition is used to parameterise and control the circumferentially-averaged radial profiles of stagnation pressure and temperature at the fan OGV exit. The developed formulation is coupled with a parametric exhaust design approach, an automatic computational mesh generator, and a compressible flow solution method. A global optimisation strategy is devised comprising methods for Design of Experiment (DOE), Response Surface Modelling (RSM), and genetic optimisation. A combined Design Space Exploration (DSE) comprising both geometric, as well as fan exit profile variables, is performed to optimise the exhaust geometry in conjunction with the fan exit profile. The developed approach is used to derive optimum exhaust geometries for a tip, mid, and hub-biased fan blade loading distribution. It is shown that the proposed formulation can ameliorate adverse transonic flow characteristics on the core after-body due to a non-uniform bypass inflow. The hub-loaded profile was found to be most penalising in terms of exhaust performance compared to the mid and tip-loaded variants. It is demonstrated that the combined fan exit profile and exhaust geometry optimisation offers significant performance improvement compared to the fixed inflow cases. The predicted performance benefits can reach up to 0.19% in terms of exhaust velocity coefficient, depending on fan loading characteristics. A notable improvement is also noted in terms of bypass nozzle discharge coefficient. This suggests that the combined optimisation can lead to an exhaust design that can satisfy the engine mass-flow rate demand with a reduced geometric throat area, thus potentially offering further exhaust size and weight benefits. [ABSTRACT FROM AUTHOR]

Background and purpose: Newly appearing lesions in multiple sclerosis (MS) may evolve into chronically active, slowly expanding lesions (SELs), leading to sustained disability progression. The aim of this study was to evaluate the incidence of newly appearing lesions developing into SELs, and their correlation to clinical evolution and treatment. Methods: A retrospective analysis of a fingolimod trial in primary progressive MS (PPMS; INFORMS, NCT 00731692) was undertaken. Data were available from 324 patients with magnetic resonance imaging scans up to 3 years after screening. New lesions at year 1 were identified with convolutional neural networks, and SELs obtained through a deformation‐based method. Clinical disability was assessed annually by Expanded Disability Status Scale (EDSS), Nine‐Hole Peg Test, Timed 25‐Foot Walk, and Paced Auditory Serial Addition Test. Linear, logistic, and mixed‐effect models were used to assess the relationship between the Jacobian expansion in new lesions and SELs, disability scores, and treatment status. Results: One hundred seventy patients had ≥1 new lesions at year 1 and had a higher lesion count at screening compared to patients with no new lesions (median = 27 vs. 22, p = 0.007). Among the new lesions (median = 2 per patient), 37% evolved into definite or possible SELs. Higher SEL volume and count were associated with EDSS worsening and confirmed disability progression. Treated patients had lower volume and count of definite SELs (β = −0.04, 95% confidence interval [CI] = −0.07 to −0.01, p = 0.015; β = −0.36, 95% CI = −0.67 to −0.06, p = 0.019, respectively). Conclusions: Incident chronic active lesions are common in PPMS, and fingolimod treatment can reduce their number. [ABSTRACT FROM AUTHOR]

Future turbo-fan engines are expected to operate at low specific thrust with high bypass ratios to improve propulsive efficiency. Typically, this can result in an increase in fan diameter and nacelle size with the associated drag and weight penalties. Therefore, relative to current designs, there is a need to develop more compact, shorter nacelles to reduce drag and weight. These designs are inherently more challenging and a system is required to explore and define the viable design space. Due to the range of operating conditions, nacelle aerodynamic design poses a significant challenge. This work presents a multi-objective optimisation approach using an evolutionary genetic algorithm for the design of new aero-engine nacelles. The novel framework includes a set of geometry definitions using Class Shape Transformations, automated aerodynamic simulation and analysis, a genetic algorithm, evaluations at various nacelle operating conditions and the inclusion of additional aerodynamic constraints. This framework has been applied to investigate the design space of nacelles for high bypass ratio aero-engines. The multi-objective optimisation was successfully demonstrated for the new nacelle design challenge and the overall system was shown to enable the identification of the viable nacelle design space. [ABSTRACT FROM AUTHOR]

Abstract The unsteady distorted flow fields generated within convoluted intakes can have a detrimental effect on the stability of an aero-engine. The frequency signature in the distorted flow field is of key importance to the engine's response. In this work, time-resolved particle image velocimetry is used to obtain the three-component velocity field at the outlet plane of two S-duct intake configurations for a range of inlet Mach numbers. Proper orthogonal decomposition of the time-resolved velocity data allows the identification of the main frequencies and coherent structures in the flow. The most energetic unsteady structures comprise an in-plane vortex switching mode, associated with a lateral oscillation of the main loss region, and a vertical oscillation of the main loss region. The switching structure occurs at a frequency of St = 0.42 and 0.32 for the high and low offset ducts, respectively. The vertical perturbation is associated with a more broadband spectrum between approximately St = 0.6 – 1.0 and St = 0.26 – 1.0 for the high and low offset configurations, respectively. The determined frequencies for these main unsteady flow structures are within the range, which is expected to be detrimental to the operating stability of an aero-engine. The results provide a novel, time-resolved dataset of synchronous velocity measurements of high spatial resolution that enables analysis of the unsteady flows at the exit of complex aero-engine intakes. [ABSTRACT FROM AUTHOR]

It is envisaged that the next generation of civil large turbofan engines will be designed for greater bypass ratios when compared to contemporary architectures. The underlying motivation is to reduce specific thrust and improve propulsive efficiency. Concurrently, the aerodynamic performance of the exhaust system is anticipated to play a key role in the success of future engine architectures. The transonic flow topology downstream of the bypass nozzle can be significantly influenced by the after-body geometry. This behavior is further complicated by the existence of the air-flow vent on the nozzle after-body which can have an impact on the performance of the exhaust system. This paper aims to investigate the aerodynamics associated with the geometry of the bypass nozzle after-body and to establish guidelines for the design of separate-jet exhausts with respect to future large turbofan engines. A parametric geometry definition has been derived based on Class-Shape Transformation (CST) functions for the representation of post-nozzle-exit components such as after-bodies, plugs, and air-flow vents. The developed method has been coupled with an automatic mesh generation and a Reynolds Averaged Navier–Stokes (RANS) flow solution method, thus devising an integrated aerodynamic design tool. A cost-effective optimization strategy has been implemented consisting of methods for Design Space Exploration (DSE), Response Surface Modeling (RSM), and Genetic Algorithms (GAs). The combined approach has been deployed to explore the aerodynamic design space associated with the bypass nozzle after-body geometry for a Very High Bypass Ratio (VHBR) turbofan engine with separate-jet exhausts. A detailed investigation has been carried out to expose the transonic flow mechanisms associated with the effect of after-body curvature combined with the impact of the air-flow vent. A set of optimum curved after-body geometries has been obtained, with each subsequently compared against their respective conical representation. The obtained results suggest that no significant performance improvements can be obtained through curving the nozzle after-body relative to the case of a conical design. However, it is shown that the application of surface curvature has the potential to unlock new parts in the design space that allow analysts to reduce the required after-body length without any loss in aerodynamic performance. The developed approach complements the existing tool-set of enabling technologies for the design and optimization of future large aero-engines, consequently leading to increased thrust and reduced Specific Fuel Consumption (SFC). [ABSTRACT FROM AUTHOR]

Background and purpose: There is increasing evidence that cardiovascular risk (CVR) contributes to disability progression in multiple sclerosis (MS). CVR is particularly prevalent in secondary progressive MS (SPMS) and can be quantified through validated composite CVR scores. The aim was to examine the cross‐sectional relationships between excess modifiable CVR, whole and regional brain atrophy on magnetic resonance imaging, and disability in patients with SPMS. Methods: Participants had SPMS, and data were collected at enrolment into the MS‐STAT2 trial. Composite CVR scores were calculated using the QRISK3 software. Prematurely achieved CVR due to modifiable risk factors was expressed as QRISK3 premature CVR, derived through reference to the normative QRISK3 dataset and expressed in years. Associations were determined with multiple linear regressions. Results: For the 218 participants, mean age was 54 years and median Expanded Disability Status Scale was 6.0. Each additional year of prematurely achieved CVR was associated with a 2.7 mL (beta coefficient; 95% confidence interval 0.8–4.7; p = 0.006) smaller normalized whole brain volume. The strongest relationship was seen for the cortical grey matter (beta coefficient 1.6 mL per year; 95% confidence interval 0.5–2.7; p = 0.003), and associations were also found with poorer verbal working memory performance. Body mass index demonstrated the strongest relationships with normalized brain volumes, whilst serum lipid ratios demonstrated strong relationships with verbal and visuospatial working memory performance. Conclusions: Prematurely achieved CVR is associated with lower normalized brain volumes in SPMS. Future longitudinal analyses of this clinical trial dataset will be important to determine whether CVR predicts future disease worsening. [ABSTRACT FROM AUTHOR]

The application of mechanical stimulation on bone tissue engineering constructs aims to mimic the native dynamic nature of bone. Although many attempts have been made to evaluate the effect of applied mechanical stimuli on osteogenic differentiation, the conditions that govern this process have not yet been fully explored. In this study, pre-osteoblastic cells were seeded on PLLA/PCL/PHBV (90/5/5 wt.%) polymeric blend scaffolds. The constructs were subjected every day to cyclic uniaxial compression for 40 min at a displacement of 400 μm, using three frequency values, 0.5, 1, and 1.5 Hz, for up to 21 days, and their osteogenic response was compared to that of static cultures. Finite element simulation was performed to validate the scaffold design and the loading direction, and to assure that cells inside the scaffolds would be subjected to significant levels of strain during stimulation. None of the applied loading conditions negatively affected the cell viability. The alkaline phosphatase activity data indicated significantly higher values at all dynamic conditions compared to the static ones at day 7, with the highest response being observed at 0.5 Hz. Collagen and calcium production were significantly increased compared to static controls. These results indicate that all of the examined frequencies substantially promoted the osteogenic capacity. [ABSTRACT FROM AUTHOR]

Low order models can be used to accelerate engineering design processes. Ideally, these surrogates should meet the conflicting requirements of large design space coverage, high accuracy and fast evaluation. Within the context of aerospace applications at transonic conditions, this can be challenging due to the associated non-linearity of the flow regime. Different methods have been investigated in the past to predict the flow-field around shapes such as airfoils or cylinders. However, they usually have reduced spatial resolution, limiting the prediction capabilities within the boundary layer which is of interest for transonic wall-bounded flows. This work proposes a novel Point-Enhanced Convolutional Neural Network (PCNN) method that combines the advantages of the well-established PointNet and convolutional neural network approaches. The PCNN model has relatively low memory requirements in the training process, preserves the spatial correlation in the domain and has the same resolution as a traditional computational method. The architecture is used for the flow-field prediction of civil aero-engine nacelles in which it is demonstrated that the flow features of peak isentropic Mach number (M i s), pre-shock isentropic Mach number and shock location (X / L n a c) are captured within Δ M i s = 0.02, Δ M i s = 0.04 , Δ X / L n a c = 0.007 , respectively. The PCNN model successfully predicts the integral parameters of the boundary layer, in which the incompressible displacement thickness, momentum thickness and shape factor are typically within 5% of the CFD. Overall, the PCNN method is demonstrated for transonic wall-bounded flows for a range of flow physics that include shock waves and shock-induced separation. [ABSTRACT FROM AUTHOR]

The next generation of turbofan aero-engines are likely to have an increase in fan diameter to reduce the specific thrust and increase the overall propulsive efficiency. More compact nacelles with possibly shorter intakes may be used to reduce weight and drag and achieve a net reduction of fuel consumption. For these compact nacelles a key consideration is the design of the short intake at the off-design conditions such as crosswind and high incidence operations. The close coupled interaction between a short intake and the fan at these off-design conditions is one of the key challenges. Previous work focused on the impact of short intake aerodynamics on the fan but there is a similar requirement to understand the impact of the fan on the viable short intake design space. This paper addresses the influence of the fan on the separation onset of the flow within a short intake under crosswind conditions. The effect of the fan on the separation characteristics of the intake boundary layer was considered both from a steady and an unsteady point of view. A hierarchy of fan computational models was used to separately assess the different aerodynamic contributions and to evaluate a net effect of the fan on the intake critical condition. Steady computational fluid dynamics analyses showed a notable positive effect of the fan on total pressure loss at post-separation conditions relative to a configuration without the fan. However, unsteady analyses revealed that fan unsteadiness has an adverse impact on the intake separation characteristics which reduces the intake critical conditions by about 15%. The main mechanisms behind the unsteady interaction were identified. Overall this work addresses, for the first time, the role of fan unsteadiness on the separation characteristics of the boundary layer within a short intake in crosswind. [ABSTRACT FROM AUTHOR]

Objective: In multiple sclerosis chronic demyelination is associated with axonal loss, and ultimately contributes to irreversible progressive disability. Enhancing remyelination may slow, or even reverse, disability. We recently trialled bexarotene versus placebo in 49 people with multiple sclerosis. While the primary MRI outcome was negative, there was converging neurophysiological and MRI evidence of efficacy. Multiple factors influence lesion remyelination. In this study we undertook a systematic exploratory analysis to determine whether treatment response – measured by change in magnetisation transfer ratio – is influenced by location (tissue type and proximity to CSF) or the degree of abnormality (using baseline magnetisation transfer ratio and T1 values). Methods: We examined treatment effects at the whole lesion level, the lesion component level (core, rim and perilesional tissues) and at the individual lesion voxel level. Results: At the whole lesion level, significant treatment effects were seen in GM but not WM lesions. Voxel‐level analyses detected significant treatment effects in WM lesion voxels with the lowest baseline MTR, and uncovered gradients of treatment effect in both WM and CGM lesional voxels, suggesting that treatment effects were lower near CSF spaces. Finally, larger treatment effects were seen in the outer and surrounding components of GM lesions compared to inner cores. Interpretation: Remyelination varies markedly within and between lesions. The greater remyelinating effect in GM lesions is congruent with neuropathological observations. For future remyelination trials, whole GM lesion measures require less complex post‐processing compared to WM lesions (which require voxel level analyses) and markedly reduce sample sizes. [ABSTRACT FROM AUTHOR]

• Applied Filtered Rayleigh Scattering (FRS) for multi-quantity flow distortion measurements in aero-engine intakes. • FRS measurements can characterize simultaneously pressure, temperature and 3D velocity across a full aerodynamic interface plane. • The proposed FRS concept measured velocity with an accuracy of 3.3% compared to particle image velocimetry data. • Introduction of machine learning can significantly accelerate FRS data processing time by up to 200 times. • FRS is a promising seeding-free technique which could be deployed for future in-flight flow distortion measurements. In-flight measurements of aerodynamic quantities are a requirement to ensure the correct scaling of Reynolds and Mach number and for the airworthiness certification of an aircraft. The ability to obtain such measurement is subject to several challenges such as instrument installation, environment, type of measurand, and spatial and temporal resolution. Given expected, more frequent use of embedded propulsion systems in the near future, the measurement technology needs to adapt for the characterization of multi-type flow distortion in complex flow, to assess the operability of air-breathing propulsion systems. To meet this increasing demand for high-fidelity experimental data, the Filtered Rayleigh Scattering (FRS) method is identified as a promising technology, as it can provide measurements of pressure, temperature and 3D velocities simultaneously, across a full Aerodynamic Interface Plane (AIP). Τhis work demonstrates the application of a novel FRS instrument, to assess the flow distortion in an S-duct diffuser, in a ground testing facility. A comparison of FRS results with Stereo-Particle Image Velocimetry (S-PIV) measurements reveals good agreement of the out of plane velocities, within 3.3 % at the AIP. Furthermore, the introduction of machine learning methods significantly accelerates the processing of the FRS data by up to 200 times, offering a substantial prospect towards real time data analysis. This study demonstrates the further development of the FRS technique, with the ultimate goal of inlet flow distortion measurements for in-flight environments. [ABSTRACT FROM AUTHOR]

Short echo time localized proton magnetic resonance spectroscopy provides quantification of brain metabolites, including N-acetyl-aspartate, myo-inositol, creatine/phosphocreatine and choline-containing compounds, which may be useful biomarkers for monitoring Alzheimer's disease. We aimed to quantify the rate of metabolite change in Alzheimer's disease, to assess factors influencing changes and to investigate the potential for serial magnetic resonance spectroscopy as an Alzheimer's disease trial biomarker. A total of 42 patients and 22 controls each had up to six magnetic resonance spectroscopy examinations over a 2-year period, using a midline posterior cingulate single-voxel point resolved spectroscopy sequence (1.5 T; time to repetition = 2000 ms; echo time = 30 ms; 192 averages). Metabolite ratios N-acetyl-aspartate:creatine/phosphocreatine, choline-containing compounds:creatine/phosphocreatine, and myo-inositol:creatine/phosphocreatine were measured using online software (PROBE-Q) and the N-acetyl-aspartate:myo-inositol ratio was derived. Baseline ratios were compared between patients and controls. A linear mixed model was used to quantify longitudinal changes and extended to assess the effect of age, disease severity and baseline use of acetylcholinesterase inhibitors. Patients and controls were matched for age (patients: 68.9 ± 7.2 years; controls: 69.1 ± 6.7 years); 71% of the patients were on acetylcholinesterase inhibitors at baseline; mean Mini-Mental State Examination for patients was 19.4 ± 4.1. A total of 307 spectra were acquired. In cross-sectional analyses, patients were significantly different from controls for N-acetyl-aspartate:creatine/phosphocreatine (11% lower, P < 0.001), N-acetyl-aspartate:myo-inositol (24% lower, P < 0.001), and myo-inositol:creatine/phosphocreatine (17% higher, P < 0.001). After adjustment for N-acetyl-aspartate:myo-inositol, none of the other variables differed significantly. In patients there was significant decline in N-acetyl-aspartate:creatine/phosphocreatine (mean: 2.2%/year; 95% confidence interval: 0.9–3.5) and N-acetyl-aspartate:myo-inositol (mean: 3.7%/year; 95% confidence interval: 1.7–5.7), with no evidence for influence by age, disease severity or acetylcholinesterase inhibitor use. There was significant excess decline in patients compared with controls only in N-acetyl-aspartate:myo-inositol (mean: 3.6%/year; 95% confidence interval: 0.8–6.4; P = 0.014). Between-subject standard deviation for N-acetyl-aspartate:myo-inositol was 0% for controls and 3.5%/year for patients; within-subject standard deviation for a 1 year, two-time-point study was 9.2%/year for both patients and controls. These results confirm that magnetic resonance spectroscopy can be used to quantify excess metabolite decline in Alzheimer's disease, which may provide a useful measure of disease progression. We found no evidence that age, disease severity or acetylcholinesterase inhibitor use influenced rate of decline, although numbers were small. The substantial variability in longitudinal measurements that drives sample size requirements is principally within-subject and technique related: technical developments to reduce this variability may make serial magnetic resonance spectroscopy a viable biomarker in clinical trials for Alzheimer's disease. [ABSTRACT FROM PUBLISHER]

Background: The envelope protein of human endogenous retrovirus W (HERV-W-Env) is expressed by macrophages and microglia, mediating axonal damage in chronic active MS lesions. Objective and Methods: This phase 2, double-blind, 48-week trial in relapsing-remitting MS with 48-week extension phase assessed the efficacy and safety of temelimab; a monoclonal antibody neutralizing HERV-W-Env. The primary endpoint was the reduction of cumulative gadolinium-enhancing T1-lesions in brain magnetic resonance imaging (MRI) scans at week 24. Additional endpoints included numbers of T2 and T1-hypointense lesions, magnetization transfer ratio, and brain atrophy. In total, 270 participants were randomized to receive monthly intravenous temelimab (6, 12, or 18 mg/kg) or placebo for 24 weeks; at week 24 placebo-treated participants were re-randomized to treatment groups. Results: The primary endpoint was not met. At week 48, participants treated with 18 mg/kg temelimab had fewer new T1-hypointense lesions (p = 0.014) and showed consistent, however statistically non-significant, reductions in brain atrophy and magnetization transfer ratio decrease, as compared with the placebo/comparator group. These latter two trends were sustained over 96 weeks. No safety issues emerged. Conclusion: Temelimab failed to show an effect on features of acute inflammation but demonstrated preliminary radiological signs of possible anti-neurodegenerative effects. Current data support the development of temelimab for progressive MS. Trial registration: CHANGE-MS: ClinicalTrials.gov: NCT02782858, EudraCT: 2015-004059-29; ANGEL-MS: ClinicalTrials.gov: NCT03239860, EudraCT: 2016-004935-18 [ABSTRACT FROM AUTHOR]

Recent trends in civil aero-engine design aim at lowering specific thrust and improving propulsive efficiency by increasing the bypass ratio and therefore, usually also the fan diameter. The integration of these larger diameter engines with the airframe is critical to exhaust performance, and it is important to include these effects in engine performance analysis. The discharge coefficient of the bypass and core nozzles of a high-bypass ratio aero-engine at idle descent conditions is investigated numerically for an aero-engine in isolation and installed on an airframe. The discharge coefficients influence the engine operating conditions and turbomachinery re-matching at these off-design conditions. The maximum difference in the bypass nozzle discharge coefficient between the installed and isolated aero-engine across the descent phase is ≃ 1.6 %. The differences in the core nozzle discharge coefficient between the installed and the reference isolated configuration are ≃ 43 % and ≃ − 5.4 % at the start and the end of the descent phase, respectively. The nozzle discharge coefficients depend on flight Mach number, incidence angle, and the nozzle pressure ratios of the fan and core nozzles. Multiple competing flow mechanisms govern the static pressure on the core nozzle base, which influences the core nozzle discharge coefficient. A novel reduced-order model is developed to estimate the core nozzle discharge coefficient for the installed configuration in idle descent conditions. This approach is based on the effective nozzle pressure ratio and can be implemented in engine performance simulations. [ABSTRACT FROM AUTHOR]