Search

Background: Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource.Methods: We did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25-65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0-6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials.gov, NCT01910259.Findings: Between Jan 29, 2015, and June 22, 2016, 445 patients were randomly allocated amiloride (n=111), fluoxetine (n=111), riluzole (n=111), or placebo (n=112). The primary analysis included 393 patients who were allocated amiloride (n=99), fluoxetine (n=96), riluzole (n=99), and placebo (n=99). No difference was noted between any active treatment and placebo in PBVC (amiloride vs placebo, 0·0% [95% CI -0·4 to 0·5; p=0·99]; fluoxetine vs placebo -0·1% [-0·5 to 0·3; p=0·86]; riluzole vs placebo -0·1% [-0·6 to 0·3; p=0·77]). No emergent safety issues were reported. The incidence of serious adverse events was low and similar across study groups (ten [9%] patients in the amiloride group, seven [6%] in the fluoxetine group, 12 [11%] in the riluzole group, and 13 [12%] in the placebo group). The most common serious adverse events were infections and infestations. Three patients died during the study, from causes judged unrelated to active treatment; one patient assigned amiloride died from metastatic lung cancer, one patient assigned riluzole died from ischaemic heart disease and coronary artery thrombosis, and one patient assigned fluoxetine had a sudden death (primary cause) with multiple sclerosis and obesity listed as secondary causes.Interpretation: The absence of evidence for neuroprotection in this adequately powered trial indicates that exclusively targeting these aspects of axonal pathobiology in patients with secondary progressive multiple sclerosis is insufficient to mitigate neuroaxonal loss. These findings argue for investigation of different mechanistic targets and future consideration of combination treatment trials. This trial provides a template for future simultaneous testing of multiple disease-modifying medicines in neurological medicine.Funding: Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership, UK Multiple Sclerosis Society, and US National Multiple Sclerosis Society. [ABSTRACT FROM AUTHOR]

Without careful consideration of aerodynamic installation effects on exhaust system performance the projected benefits of high bypass ratio engines may not be achievable. This work presents a computational study of propulsion system integration in order to quantify the effect that aircraft installation has on the aerodynamic performance of separate-jet aero-engine exhaust systems. Within this study the sensitivity of exhaust nozzle performance metrics to aircraft incidence and under wing position were investigated for two engines of different specific thrust. Upon installation, thrust generation was found to be beneficial or detrimental relative to an isolated engine depending on the position of the engine relative to the wing leading edge. The dominant installation effect was observed on the exhaust afterbodies and, over the range of engine positions investigated at cruise conditions, the installed modified velocity coefficient was shown to vary up to 1% relative to an isolated engine. Furthermore, due to variations in the core nozzle mass flow rate by up to 10% relative to an isolated engine, it is concluded that aerodynamic installation effects need to be taken into consideration when sizing the core nozzle in order to ensure engine operability. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To investigate the relationship between brain volume and disability worsening over ≥3 years in the natural history of primary progressive multiple sclerosis using data from the placebo group of the INFORMS trial (n = 487; clinicaltrials.gov NCT00731692). Methods: Magnetic resonance imaging scans were collected annually. Brain volume loss was determined using SIENA. Patients were stratified by baseline normalized brain volume after adjusting for demographic and disease‐burden covariates. Results: Baseline normalized brain volume was predictive of disability worsening: Risk of 3‐month confirmed disability progression was reduced by 36% for high versus low baseline normalized brain volume (Cox's model hazard ratio 0.64, P = 0.0339; log‐rank test: P = 0.0297). Moreover, on‐study brain volume loss was significantly associated with disability worsening (P = 0.012) and was evident in patients with or without new lesions or relapses. Brain volume loss depended significantly on baseline T2 lesion volume (P < 0.0001). Despite low inflammatory activity at baseline (13% of patients had gadolinium‐enhancing lesions) and throughout the study (mean 0.5 new/enlarging T2 lesions and 172 mm3 T2 lesion volume increase per year), baseline T2 lesion volume was substantial (mean 10 cm3). Lower normalized brain volume at baseline correlated with higher baseline T2 volume and older age (both P < 0.0001). Interpretation: Baseline brain volume and the rate of ongoing brain atrophy are significantly associated with disability worsening in primary progressive multiple sclerosis. Brain volume loss is significantly related to baseline T2 lesion volume, but partially independent of new lesion activity, which might explain the limited efficacy of anti‐inflammatory treatment. [ABSTRACT FROM AUTHOR]

Inlet flow distortion is expected to play a major role in future aircraft architectures where complex air induction systems are required to couple the engine with the airframe. The highly unsteady distortions generated by such intake systems can be detrimental to engine performance and were previously linked with loss of engine stability and potentially catastrophic consequences. During aircraft design, inlet flow distortion is typically evaluated at the aerodynamic interface plane, which is defined as a cross-flow plane located at a specific upstream distance from the engine fan. Industrial testing currently puts more emphasis on steady state distortions despite the fact that, historically, unsteady distortions were acknowledged as equally important. This was partially due to the limitations of intrusive measurement methods to deliver unsteady data of high spatial resolution in combination with their high cost and complexity. However, as the development of aircraft with fuselage-integrated engine concepts progresses, the combination of different types of flow distortions is expected to have a strong impact on the engine's stability margin. Therefore, the need for novel measurement methods able to meet the anticipated demand for more comprehensive flow information is now more critical than ever. In reviewing the capabilities of various non-intrusive methods for inlet distortion measurements, Filtered Rayleigh Scattering (FRS) is found to have the highest potential for synchronously characterising multiple types of inlet flow distortions, since the method has the proven ability to simultaneously measure velocity, static pressure and temperature fields in challenging experimental environments. The attributes of the FRS method are further analysed aiming to deliver a roadmap for its application on ground-based and in-flight measurement environments. [ABSTRACT FROM AUTHOR]

Abstract: The Minimal Interval Resonance Imaging in Alzheimer''s Disease (MIRIAD) dataset is a series of longitudinal volumetric T1 MRI scans of 46 mild–moderate Alzheimer''s subjects and 23 controls. It consists of 708 scans conducted by the same radiographer with the same scanner and sequences at intervals of 2, 6, 14, 26, 38 and 52weeks, 18 and 24months from baseline, with accompanying information on gender, age and Mini Mental State Examination (MMSE) scores. Details of the cohort and imaging results have been described in peer-reviewed publications, and the data are here made publicly available as a common resource for researchers to develop, validate and compare techniques, particularly for measurement of longitudinal volume change in serially acquired MR. [Copyright &y& Elsevier]

Summary: Background: Monoclonal antibody therapy against α4β-integrin is efficacious in patients with multiple sclerosis (MS) with some safety concerns. We assessed the safety and efficacy of firategrast, a small oral anti-α4β-integrin molecule, in patients with relapsing remitting MS. Methods: We did a multicentre, phase 2, randomised, double-blind, placebo-controlled, dose-ranging study in participants with clinically definite relapsing-remitting MS. A 24-week treatment period was followed by 12 weeks of core follow-up and 40 weeks of extended follow-up. Participants were randomly assigned, via computer-generated block randomisation in a 1:2:2:2 ratio, to receive one of four treatments twice a day: firategrast 150 mg, firategrast 600 mg, or firategrast 900 mg (women) or 1200 mg (men), or placebo. Brain scans were obtained at 4-week intervals to the end of core follow-up. The primary outcome was cumulative number of new gadolinium-enhancing brain lesions during the treatment phase and was analysed using a generalised linear model with an underlying negative binomial distribution, adjusted for sex, baseline number of new gadolinium-enhancing lesions, and country. This study is registered with ClinicalTrials.gov, NCT00395317. Findings: Of 343 individuals enrolled, 49 received firategrast 150 mg, 95 received firategrast 600 mg, 100 received firategrast 900 mg or 1200 mg, and 99 received placebo. A 49% reduction (95% CI 21·2–67·6; p=0·0026) in the cumulative number of new gadolinium-enhancing lesions was seen for the 900 mg or 1200 mg firategrast group (n=92, mean number of lesions 2·69 [SE 1·18]) versus the placebo group (90, 5·31 [1·18]). In the 600 mg group (86, 4·12 [SE 1·19]), a non-significant 22% reduction (95% CI −21·3 to 49·7; p=0·2657) occurred in mean number of new gadolinium-enhanced lesions relative to placebo; for the 150 mg group (47, 9·51 [SE 1·24]), a 79% increase (95% CI 4·1–308·1; p=0·0353) occurred relative to placebo. Firategrast was generally well tolerated at all doses. The frequency of all adverse events was similar across all treatment groups except for an increased rate of urinary tract infections in the high-dose firategrast group. No cases of progressive multifocal leukoencephalopathy or evidence of reactivation of JC virus were identified. Interpretation: This study showed efficacy on imaging endpoints for firategrast at the highest dose tested, and suggests that further investigation of oral short-acting α4β integrin blockade therapies is warranted. Funding: GlaxoSmithKline. [Copyright &y& Elsevier]

Diffusion tensor imaging (DTI), a magnetic resonance imaging technique, is used to infer major axonal projections in the macaque and human brain. This study investigates the feasibility of using known macaque anatomical connectivity as a “gold-standard” for the evaluation of DTI tractography methods. Connectivity information is determined from the DTI data using fast marching tractography (FMT), a novel tract-tracing (tractography) method. We show for the first time that it is possible to determine, in an entirely noninvasive manner, anatomical connection pathways and maps of an anatomical connectivity metric in the macaque brain using a standard clinical scanner and that these pathways are consistent with known anatomy. Analogous human anatomical connectivity is also presented for the first time using the FMT method, and the results are compared. The current limitations of the methodology and possibilities available for further studies are discussed. [Copyright &y& Elsevier]

It is envisaged that the next generation of civil aero-engines will employ high bypass ratios to lower specific thrust and improve propulsive efficiency. This trend is likely to be accompanied with the integration of compact nacelle and exhausts in podded under-wing installation positions that are close coupled to the airframe. This leads to the requirement for a comprehensive methodology able to predict aerodynamic performance for combined airframe-engine architectures. This paper presents a novel thrust and drag accounting approach for the aerodynamic analysis of integrated airframe-engine systems. An integral metric is synthesised based on the concept of net vehicle force. This is accomplished through the consolidation of aerodynamic coefficients, combined with the engine cycle characteristics obtained from a thermodynamic matching model. The developed approach is coupled with an in-house tool for the aerodynamic design and analysis of installed aero-engines. This framework is deployed to quantify the impact of engine installation position on the aerodynamic performance of a future large turbofan installed on a commercial wide-body airframe. The governing flow mechanisms are identified and their influence is decomposed in terms of the impact on airframe, nacelle, and exhaust performance. It is shown that it is essential to include the impact of installation on the exhaust for the correct determination of overall airframe-engine performance. The difference in net vehicle force for a close coupled position can reach up to -0.70% of nominal standard net thrust relative to a representative baseline engine location. [ABSTRACT FROM AUTHOR]

In order to increase propulsive efficiency, and hence reduce fuel consumption, future aero-engines are expected to operate with higher bypass ratios and larger fan diameters relative to current in-service engines. As such, propulsion systems are likely to be more closely-coupled with the airframe which is expected to accentuate detrimental aerodynamic interference effects between the engine and airframe. It is therefore crucial that the design of future aero-engine exhaust systems is considered as part of an engine-airframe configuration in order to ensure that the expected benefits of high BPR engines are realised. This work presents the aerodynamic performance and evaluation of a set of novel exhaust systems within complete engine-airframe configurations. The introduction of non-axisymmetric exhaust systems was shown to mitigate the aerodynamic penalties associated with closely-coupled propulsion systems at cruise conditions. Relative to an axisymmetric baseline configuration, the introduction of non-axisymmetric bypass and core nozzles were found to increase the net vehicle force of the engine-airframe configuration by 0.8% and 0.6% respectively. As a result of this work, it can be concluded that non-axisymmetric exhaust systems represent a viable method for reducing aircraft cruise fuel burn. [ABSTRACT FROM AUTHOR]

The inherent mathematical smoothness of intuitive class shape transformation (iCST) curves has been shown to be suitable for the design of aerodynamic shapes. However, this property means that any changes to a constraint are not local but will result in a modification to the whole curve. This poses a problem to the aerodynamic designer when different parts of the curve are required to fulfil particular design requirements. A Hybrid iCST (HiCST) parameterisation approach is proposed which allows two sections of a single aero-line curve to be decoupled, without geometric discontinuity, whilst maintaining the dimensionality of a design problem. The HiCST approach has been tested on two key aerodynamic components of an aero-engine. Firstly, a design space exploration and optimisation were carried out for an aero-engine fan cowl. A comparison of Pareto fronts showed a 3.9% reduction in the minimum achievable nacelle drag from the iCST to the HiCST parameterisation. Secondly, aero-engine intakes were designed with both the iCST and HiCST parameterisations. The HiCST intake showed improved aerodynamic performance in terms of DC 60 and IPR and proved more insensitive to changes in massflow and incidence. This development of the method for an aero-engine fan cowl and intake highlights the potential aerodynamic benefit from the proposed HiCST method. [ABSTRACT FROM AUTHOR]

Future civil air vehicles are likely to feature propulsion systems which are more closely integrated with the airframe. For a podded underwing configuration, this close coupling is expected to require non-axisymmetric design capabilities for the aero-engine exhaust system. This work presents the development of a novel parametric representation of non-axisymmetric aero-engine exhaust system geometries based on Intuitive Class Shape Transformation (iCST) curves. An exhaust design method was established and aerodynamic analyses of a range of non-axisymmetric configurations was demonstrated. At typical flight conditions, the introduction of non-axisymmetric separate-jet nozzles was shown to increase the engine net propulsive force by 0.12% relative to an axisymmetric nozzle. [ABSTRACT FROM AUTHOR]

Background: Monoclonal antibody therapy against α4β-integrin is efficacious in patients with multiple sclerosis (MS) with some safety concerns. We assessed the safety and efficacy of firategrast, a small oral anti-α4β-integrin molecule, in patients with relapsing remitting MS.Methods: We did a multicentre, phase 2, randomised, double-blind, placebo-controlled, dose-ranging study in participants with clinically definite relapsing-remitting MS. A 24-week treatment period was followed by 12 weeks of core follow-up and 40 weeks of extended follow-up. Participants were randomly assigned, via computer-generated block randomisation in a 1:2:2:2 ratio, to receive one of four treatments twice a day: firategrast 150 mg, firategrast 600 mg, or firategrast 900 mg (women) or 1200 mg (men), or placebo. Brain scans were obtained at 4-week intervals to the end of core follow-up. The primary outcome was cumulative number of new gadolinium-enhancing brain lesions during the treatment phase and was analysed using a generalised linear model with an underlying negative binomial distribution, adjusted for sex, baseline number of new gadolinium-enhancing lesions, and country. This study is registered with ClinicalTrials.gov, NCT00395317.Findings: Of 343 individuals enrolled, 49 received firategrast 150 mg, 95 received firategrast 600 mg, 100 received firategrast 900 mg or 1200 mg, and 99 received placebo. A 49% reduction (95% CI 21·2-67·6; p=0·0026) in the cumulative number of new gadolinium-enhancing lesions was seen for the 900 mg or 1200 mg firategrast group (n=92, mean number of lesions 2·69 [SE 1·18]) versus the placebo group (90, 5·31 [1·18]). In the 600 mg group (86, 4·12 [SE 1·19]), a non-significant 22% reduction (95% CI -21·3 to 49·7; p=0·2657) occurred in mean number of new gadolinium-enhanced lesions relative to placebo; for the 150 mg group (47, 9·51 [SE 1·24]), a 79% increase (95% CI 4·1-308·1; p=0·0353) occurred relative to placebo. Firategrast was generally well tolerated at all doses. The frequency of all adverse events was similar across all treatment groups except for an increased rate of urinary tract infections in the high-dose firategrast group. No cases of progressive multifocal leukoencephalopathy or evidence of reactivation of JC virus were identified.Interpretation: This study showed efficacy on imaging endpoints for firategrast at the highest dose tested, and suggests that further investigation of oral short-acting α4β integrin blockade therapies is warranted.Funding: GlaxoSmithKline. [ABSTRACT FROM AUTHOR]

Background: Deep grey matter pathology is a key driver of disability worsening in people with multiple sclerosis. Quantitative susceptibility mapping (QSM) is an advanced magnetic resonance imaging (MRI) technique which quantifies local magnetic susceptibility from variations in phase produced by changes in the local magnetic field. In the deep grey matter, susceptibility has previously been validated against tissue iron concentration. However, it currently remains unknown whether susceptibility is abnormal in older progressive MS cohorts, and whether it correlates with disability., Objectives: To investigate differences in mean regional susceptibility in deep grey matter between people with secondary progressive multiple sclerosis (SPMS) and healthy controls; to examine in patients the relationships between deep grey matter susceptibility and clinical and imaging measures of disease severity., Methods: Baseline data from a subgroup of the MS-STAT2 trial (simvastatin vs. placebo in SPMS, NCT03387670) were included. The subgroup underwent clinical assessments and an advanced MRI protocol at 3T. A cohort of age-matched healthy controls underwent the same MRI protocol. Susceptibility maps were reconstructed using a robust QSM pipeline from multi-echo 3D gradient-echo sequence. Regions of interest (ROIs) in the thalamus, globus pallidus and putamen were segmented from 3D T1-weighted images, and lesions segmented from 3D fluid-attenuated inversion recovery images. Linear regression was used to compare susceptibility from ROIs between patients and controls, adjusting for age and sex. Where significant differences were found, we further examined the associations between ROI susceptibility and clinical and imaging measures of MS severity., Results: 149 SPMS (77% female; mean age: 53 yrs; median Expanded Disability Status Scale (EDSS): 6.0 [interquartile range 4.5-6.0]) and 33 controls (52% female, mean age: 57) were included.Thalamic susceptibility was significantly lower in SPMS compared to controls: mean (SD) 28.6 (12.8) parts per billion (ppb) in SPMS vs. 39.2 (12.7) ppb in controls; regression coefficient: -12.0 [95% confidence interval: -17.0 to -7.1], p < 0.001. In contrast, globus pallidus and putamen susceptibility were similar between both groups.In SPMS, a 10 ppb lower thalamic susceptibility was associated with a +0.13 [+0.01 to +0.24] point higher EDSS (p < 0.05), a -2.4 [-3.8 to -1.0] point lower symbol digit modality test (SDMT, p = 0.001), and a -2.4 [-3.7 to -1.1] point lower Sloan low contrast acuity, 2.5% (p < 0.01).Lower thalamic susceptibility was also strongly associated with a higher T2 lesion volume (T2LV, p < 0.001) and lower normalised whole brain, deep grey matter and thalamic volumes (all p < 0.001)., Conclusions: The reduced thalamic susceptibility found in SPMS compared to controls suggests that thalamic iron concentrations are lower at this advanced stage of the disease. The observed relationships between lower thalamic susceptibility and more severe physical, cognitive and visual disability suggests that reductions in thalamic iron may correlate with important mechanisms of clinical disease progression. Such mechanisms appear to intimately link reductions in thalamic iron with higher T2LV and the development of thalamic atrophy, encouraging further research into QSM-derived thalamic susceptibility as a biomarker of disease severity in SPMS., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: 1 H-magnetic resonance spectroscopy ( 1 H-MRS) may provide a direct index for the testing of medicines for neuroprotection and drug mechanisms in multiple sclerosis (MS) through measures of total N-acetyl-aspartate (tNAA), total creatine (tCr), myo-inositol (mIns), total-choline (tCho), and glutamate + glutamine (Glx). Neurometabolites may be associated with clinical disability with evidence that baseline neuroaxonal integrity is associated with upper limb function and processing speed in secondary progressive MS (SPMS)., Purpose: To assess the effect on neurometabolites from three candidate drugs after 96-weeks as seen by 1 H-MRS and their association with clinical disability in SPMS., Study-Type: Longitudinal., Population: 108 participants with SPMS randomized to receive neuroprotective drugs amiloride [mean age 55.4 (SD 7.4), 61% female], fluoxetine [55.6 (6.6), 71%], riluzole [54.6 (6.3), 68%], or placebo [54.8 (7.9), 67%]., Field Strength/sequence: 3-Tesla. Chemical-shift-imaging 2D-point-resolved-spectroscopy (PRESS), 3DT1., Assessment: Brain metabolites in normal appearing white matter (NAWM) and gray matter (GM), brain volume, lesion load, nine-hole peg test (9HPT), and paced auditory serial addition test were measured at baseline and at 96-weeks., Statistical Tests: Paired t-test was used to analyze metabolite changes in the placebo arm over 96-weeks. Metabolite differences between treatment arms and placebo; and associations between baseline metabolites and upper limb function/information processing speed at 96-weeks assessed using multiple linear regression models. P-value<0.05 was considered statistically significant., Results: In the placebo arm, tCho increased in GM (mean difference = -0.32 IU) but decreased in NAWM (mean difference = 0.13 IU). Compared to placebo, in the fluoxetine arm, mIns/tCr was lower (β = -0.21); in the riluzole arm, GM Glx (β = -0.25) and Glx/tCr (β = -0.29) were reduced. Baseline tNAA(β = 0.22) and tNAA/tCr (β = 0.23) in NAWM were associated with 9HPT scores at 96-weeks., Data Conclusion: 1 H-MRS demonstrated altered membrane turnover over 96-weeks in the placebo group. It also distinguished changes in neuro-metabolites related to gliosis and glutaminergic transmission, due to fluoxetine and riluzole, respectively. Data show tNAA is a potential marker for upper limb function., Level of Evidence: 1 TECHNICAL EFFICACY: Stage 4., (© 2023 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Low serum levels of 25-hydroxyvitamin D [25(OH)D] and low sunlight exposure are known risk factors for the development of multiple sclerosis. Add-on vitamin D supplementation trials in established multiple sclerosis have been inconclusive. The effects of vitamin D supplementation to prevent multiple sclerosis is unknown. We aimed to test the hypothesis that oral vitamin D3 supplementation in high-risk clinically isolated syndrome (abnormal MRI, at least three T2 brain and/or spinal cord lesions), delays time to conversion to definite multiple sclerosis, that the therapeutic effect is dose-dependent, and that all doses are safe and well tolerated. We conducted a double-blind trial in Australia and New Zealand. Eligible participants were randomized 1:1:1:1 to placebo, 1000, 5000 or 10 000 international units (IU) of oral vitamin D3 daily within each study centre (n = 23) and followed for up to 48 weeks. Between 2013 and 2021, we enrolled 204 participants. Brain MRI scans were performed at baseline, 24 and 48 weeks. The main study outcome was conversion to clinically definite multiple sclerosis based on the 2010 McDonald criteria defined as either a clinical relapse or new brain MRI T2 lesion development. We included 199 cases in the intention-to-treat analysis based on assigned dose. Of these, 116 converted to multiple sclerosis by 48 weeks (58%). Compared to placebo, the hazard ratios (95% confidence interval) for conversion were 1000 IU 0.87 (0.50, 1.50); 5000 IU 1.37 (0.82, 2.29); and 10 000 IU 1.28 (0.76, 2.14). In an adjusted model including age, sex, latitude, study centre and baseline symptom number, clinically isolated syndrome onset site, presence of infratentorial lesions and use of steroids, the hazard ratios (versus placebo) were 1000 IU 0.80 (0.45, 1.44); 5000 IU 1.36 (0.78, 2.38); and 10 000 IU 1.07 (0.62, 1.85). Vitamin D3 supplementation was safe and well tolerated. We did not demonstrate reduction in multiple sclerosis disease activity by vitamin D3 supplementation after a high-risk clinically isolated syndrome., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Total ankle arthroplasty is the gold standard surgical treatment for severe ankle arthritis and fracture. However, revision surgeries due to the in vivo failure of the ankle implant are a serious concern. Extreme bone density loss due to bone remodelling is one of the main reasons for in situ implant loosening, with aseptic loosening of the talar component being one of the primary reasons for total ankle arthroplasty revisions. This study is aimed at determining the performance and potential causes of failure of the talar component. Herein, we investigated the stress, strain, and bone density changes that take place in the talus bone during the first 6 months of bone remodelling due to the total ankle arthroplasty procedure. Computed tomography scans were used to generate the 3D geometry used in the finite element (FE) model of the Intact and implanted ankle. The Scandinavian Total Ankle Replacement (STAR™) CAD files were generated, and virtual placement within bone models was done following surgical guidelines. The dorsiflexion physiological loading condition was investigated. The cortical region of the talus bone was found to demonstrate the highest values of stress (5.02 MPa). Next, the adaptive bone remodelling theory was used to predict bone density changes over the initial 6-month post-surgery. A significant change in bone density was observed in the talus bone due to bone remodelling. The observed quantitative changes in talus bone density over 6-month period underscore potential implications for implant stability and fracture susceptibility. These findings emphasise the importance of considering such biomechanical factors in ankle implant design and clinical management.

Vertebral compression fractures are one of the most severe clinical consequences of osteoporosis and the most common fragility fracture afflicting 570 and 1070 out of 100,000 men and women worldwide, respectively. Vertebroplasty (VP), a minimally invasive surgical procedure that involves the percutaneous injection of bone cement, is one of the most efficacious methods to stabilise osteoporotic vertebral compression fractures. However, postoperative fracture has been observed in up to 30% of patients following VP. Therefore, this study aims to investigate the effect of different injectable bone cement formulations on the stress distribution within the vertebrae and intervertebral discs due to VP and consequently recommend the optimal cement formulation. To achieve this, a 3D finite element (FE) model of the T11-L1 vertebral body was developed from computed tomography scan data of the spine. Osteoporotic bone was modeled by reducing the Young's modulus by 20% in the cortical bone and 74% in cancellous bone. The FE model was subjected to different physiological movements, such as extension, flexion, bending, and compression. The osteoporotic model caused a reduction in the average von Mises stress compared with the normal model in the T12 cancellous bone and an increment in the average von Mises stress value at the T12 cortical bone. The effects of VP using different formulations of a novel injectable bone cement were modeled by replacing a region of T12 cancellous bone with the materials. Due to the injection of the bone cement at the T12 vertebra, the average von Mises stresses on cancellous bone increased and slightly decreased on the cortical bone under all loading conditions. The novel class of bone cements investigated herein demonstrated an effective restoration of stress distribution to physiological levels within treated vertebrae, which could offer a potential superior alternative for VP surgery as their anti-osteoclastogenic properties could further enhance the appeal of their fracture treatment and may contribute to improved patient recovery and long-term well-being., (© 2024 The Authors. Journal of Biomedical Materials Research Part B: Applied Biomaterials published by Wiley Periodicals LLC.)

Mechanical characterization experiments of brain tissue are performed to understand the mechanical behavior of brain tissue during normal physiology and pathophysiological processes including traumatic brain injury. Normal, healthy, undamaged, unfixed brain tissue specimens are required for these mechanical characterization experiments to ensure the properties being measured are not from damaged/diseased tissue which may lead to inaccurate and unreliable results regarding the mechanical behavior of healthy undamaged brain tissue. The process of excising brain tissue from the cranial vault of mouse cadavers can induce lacerations in the tissue that may affect its mechanical behavior. Therefore, it is imperative that brain tissue samples are excised without inducing damage to the tissue so that the normal undamaged mechanical properties can be measured. Here, a method to excise the entire intact mouse brain is presented:•The scalp is resected exposing the anterior portion of the skull.•Cranial bone is resected by incising along the cranial sutures and using the scalpel blade to remove the cranial segments.•Connective tissue is resected and the brain is removed from the cranial vault., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Traumatic spinal cord injuries result from high impact forces acting on the spine and are proceeded by an extensive secondary inflammatory response resulting in motor, sensory, and autonomic dysfunction. Experimental in vivo traumatic spinal cord injuries in rodents using a contusion model have been extremely useful in elucidating the underlying pathophysiology of these injuries. However, the relationship between the pathophysiology and the biomechanical factors is still not well understood. Therefore, the aim of this research is to provide a comprehensive analysis of the biomechanics of traumatic spinal cord injury in a rat contusion model. This is achieved through the development and validation of a finite element model of the thoracic rat spinal cord and subsequently simulating controlled cortical impact-induced traumatic spinal cord injury. The effects of impactor velocity, depth, and geometry on the resulting stresses and strains within the spinal cord are investigated. Our results show that increasing impactor depth results in larger stresses and strains within the spinal cord tissue as expected. Further, for the first time ever our results show that impactor geometry (spherical versus cylindrical) plays an important role in the distribution and magnitude of stresses and strains within the cord. Therefore, finite element modelling can be a powerful tool used to predict stresses and strains that occur in spinal cord tissue during trauma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The occurrence of periprosthetic femoral fractures (PFF) has increased in people with osteoporosis due to decreased bone density, poor bone quality, and stress shielding from prosthetic implants. PFF treatment in the elderly is a genuine concern for orthopaedic surgeons as no effective solution currently exists. Therefore, the goal of this study was to determine whether the design of a novel advanced medicinal therapeutic device (AMTD) manufactured from a polymeric blend in combination with a fracture fixation plate in the femur is capable of withstanding physiological loads without failure during the bone regenerative process. This was achieved by developing a finite element (FE) model of the AMTD together with a fracture fixation assembly, and a femur with an implanted femoral stem. The response of both normal and osteoporotic bone was investigated by implementing their respective material properties in the model. Physiological loading simulating the peak load during standing, walking, and stair climbing was investigated. The results showed that the fixation assembly was the prime load bearing component for this configuration of devices. Within the fixation assembly, the bone screws were found to have the highest stresses in the fixation assembly for all the loading conditions. Whereas the stresses within the AMTD were significantly below the maximum yield strength of the device's polymeric blend material. Furthermore, this study also investigated the performance of different fixation assembly materials and found Ti-6Al-4V to be the optimal material choice from those included in this study., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Convoluted aero-engine intakes are often required to enable closer integration between engine and airframe. Although the majority of previous research focused on the distortion of S-duct intakes with undistorted inlet conditions, there is a need to investigate the impact of more challenging inlet conditions at which the intake duct is expected to operate. The impact of inlet vortices and total pressure profiles on the inherent unsteady flow distortion of an S-duct intake was assessed with stereo particle image velocimetry. Inlet vortices disrupted the characteristic flow switching mode but had a modest impact on the peak levels and unsteady fluctuations. Non-uniform inlet total pressure profiles increased the peak swirl intensity and its unsteadiness. The frequency of swirl angle fluctuations was sensitive to the azimuthal orientation of the non-uniform total pressure distribution. The modelling of peak distortion with the extreme value theory revealed that although for some inlet configurations the measured peak swirl intensity was similar, the growth rate of the peak values beyond the experimental observations was substantially different and it was related with the measured flow unsteadiness. This highlights the need of unsteady swirl distortion measurements and the use of statistical models to assess the time-invariant peak distortion levels. Overall, the work shows it is vital to include the effect of the inlet flow conditions as it substantially alters the characteristics of the complex intake flow distortion., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© IMechE 2022.)

Background and Objective: To explore the relationship between slowly expanding lesions (SELs) on MRI and disability in secondary progressive multiple sclerosis (SPMS)., Methods: We retrospectively studied 345 patients with SPMS enrolled in the MS-SMART trial. They underwent brain MRI at baseline and at 24 and 96 weeks. Definite SELs were defined as concentrically expanding T2 lesions, as assessed by nonlinear deformation of volumetric T1-weighted images. Associations of SEL volumes with other MRI metrics and disability were assessed through Pearson correlations and regression analyses., Results: Averaged across patients, 29% of T2 lesions were classified as being definite SELs. A greater volume of definite SELs correlated with a higher total baseline T2 lesion volume ( r = 0.55, p < 0.001) and percentage brain volume reduction ( r = -0.26, p < 0.001), a higher number of new persisting T1 black holes ( r = 0.19, p < 0.001), and, in a subset of 106 patients, with a greater reduction in magnetization transfer ratio (adjusted difference 0.52, p < 0.001). In regression analyses, a higher definite SEL volume was associated with increasing disability, as assessed by the Expanded Disability Status Scale (β = 0.23, p = 0.020), z scores of the Multiple Sclerosis Functional Composite (β = -0.47, p = 0.048), Timed 25-Foot Walk Test (β = -2.10, p = 0.001), and Paced Auditory Serial Addition Task (β = -0.27, p = 0.006), and increased risk of disability progression (odds ratio 1.92, p = 0.025)., Discussion: Definite SELs represent almost one-third of T2 lesions in SPMS. They are associated with neurodegenerative MRI markers and related to clinical worsening, suggesting that they may contribute to disease progression and be a new target for therapeutic interventions., (© 2022 American Academy of Neurology.)

The liver is the most commonly injured abdominal organ following either blunt or penetrating impact. Current mechanical properties available in the literature are typically only measured at low strain rates, low strains, or use linear viscoelastic models. There is also a dearth of high-rate, large strain, viscoelastic data available for liver tissue which are required to model the deformation of the liver during high-rate impacts. Furthermore, the issue of whether mouse liver's mechanical properties are sex-dependent has not been addressed previously. Here, we present the first in vitro sex- and age-controlled mechanical characterisation of mixed-strain (C57BL and wild-type) mouse liver tissue at a localised length scale using large-deformation and high strain rate micro-indentation. We also investigated the effects of age on the mechanical properties of liver tissue. Force-relaxation experiments were performed on both male and female mouse livers up to 35% strain at 10/s and allowed to relax for 1s. The neo-Hookean based quasi-linear viscoelastic model was fitted to the experimental data to determine the large-strain behaviour of the tissue. A comprehensive statistical analysis was performed to determine whether any significant differences existed for (i) the short-term shear moduli and (ii) long-term shear moduli between 10 weeks-old male and female mouse livers, and (iii) the short-term and (iv) long-term shear moduli for 6, 10, and 56 weeks-old mouse livers. No significant differences were found between the mechanical properties in the sex groups. The 56 weeks-old liver tissue was found to be significantly stiffer than the 6 weeks-old liver tissue, but not the 10 weeks-old., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Understanding the behaviour of soft tissues under large strains and high loading rates is crucial in the field of biomechanics in order to investigate tissue behaviour during pathological processes such as traumatic brain injury (TBI). It is, therefore, necessary to characterise the mechanical properties of such tissues under large strain and high strain rates that are similar to those experienced during injury. However, there is a dearth of large strain and high rate mechanical properties for brain tissue. This is likely driven by the lack of commercially available equipment to perform such tests and the difficulties associated with developing appropriate custom-built apparatus. Here, we address this problem by presenting a novel, custom-built micro-indentation apparatus that is capable of characterising the mechanical properties of brain tissue up to 35% at 100/s with a spatial resolution of 250 µm. Indentations were performed on the cortex and cerebellum of five-week-old mouse brains up to 35% strain at 1, 10, and 100/s. Three hyperelastic models were fitted to the experimental data that demonstrate the strong rate-dependency of the tissue. The neo-Hookean shear modulus for the cortex tissue was calculated to be 2.36 ± 0.46, 3.64 ± 0.48, and 8.98 ± 0.66 kPa (mean ± SD) for 1, 10, and 100/s, respectively. Similarly, the cerebellum shear modulus was calculated to be 1.12 ± 0.26, 1.58 ± 0.32, 3.10 ± 0.70 kPa for 1, 10, and 100/s, respectively. Student's t-tests were used to show statistically significant differences between the cortex and cerebellum at each strain rate. Furthermore, we discuss the apparent strain-softening effect in the 100/s force-displacement curves for both regions after approximately 30% strain., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Although the aetiology of multiple sclerosis (MS) remains elusive, it is clear that Epstein Barr virus (EBV) and possibly other viruses play a role in the pathogenesis of MS. Laboratory evidence suggests that human endogenous retroviruses (HERVs) could also have a role, but no interventional therapy has determined what will happen if HERVs are suppressed. Recent epidemiological evidence indicates patients with HIV infection have a significantly lower risk of developing MS and that HIV antiretroviral therapies may be coincidentally inhibiting HERVs, or other retroelements, that could be implicated in MS., Objectives: To systematically investigate the effects of an HIV integrase strand inhibitor, raltegravir, on the number of gadolinium (Gd)-enhanced MRI lesions in people with active relapsing MS., Methods: This is a Phase 2a clinical trial where twenty participants were enrolled in a 3 month baseline phase followed by 3 months of treatment with raltegravir 400 mg twice a day. Patients had monthly Gd-enhanced MRI, saliva collection to test for EBV shedding, blood sampling for safety monitoring, virology (including HERVs), measurement of immunological and inflammatory markers; and physical, neurological and quality-of-life assessments., Results: All patients completed the six months trial period.The primary outcome measure of MS disease activity was the number of Gd-enhancing lesions observed, and raltegravir had no significant effect on the rate of development of Gd-enhancing lesions during the treatment phase compared with the baseline phase. Additionally, there was no change in secondary outcomes of either disability or quality-of-life measures that could reasonably be attributed to the intervention. There was a significant positive between HERV-W/MSRV (multiple sclerosis related virus) Gag Flix (Fluorescence index) B cells and the number of Gd-enhanced lesions at any visit (p = 0.029), which was independent of any potential influence of the trial drug administration. Regarding EBV shedding, there was no significant correlation between the amount of EBV shedding and the number of lesions. No change was detected in inflammatory markers (IL-8, IL-1β, IL-6, IL-10, TNF, IL-12p70 and HCRP), which were all within normal limits both before and after the intervention. Serum CD163 expression was also unchanged by raltegravir., Conclusions: Raltegravir did not have any impact on MS disease activity. This could be due to the choice of antiretroviral agent used in this study, the need for a combination of agents, as used in treating HIV infection, the short treatment period or dosing regimen, or the lack of a role of HERV expression in MS once the disease is established. Borderline significance for the association between EBV shedding and the total number of lesions, probably driven by new lesion development, may indicate EBV shedding as a marker of inflammatory disease activity. In conclusion, interesting correlations between HERV-W markers, EBV shedding and new MRI lesions, independent from treatment effects, were found., (Copyright © 2018. Published by Elsevier B.V.)

Traumatic brain injuries, the leading cause of death and disability in children and young adults, are the result of a rapid acceleration or impact of the head. In recent years, a global effort to better understand the biomechanics of TBI has been undertaken, with many laboratories creating detailed computational models of the head and brain. For these models to produce realistic results they require accurate regional constitutive data for brain tissue. However, there are large differences in the mechanical properties reported in the literature. These differences are likely due to experimental parameters such as specimen age, brain region, species, test protocols, and fiber direction which are often not reported. Furthermore, there is a dearth of reported viscoelastic properties for brain tissue at large-strain and high rates. Mouse, rat, and pig brains are impacted at 10/s to a strain of ~36% using a custom-built micro-indenter with a 125 μm radius. It is shown that the resultant mechanical properties are dependent on specimen-age, species, and region, under identical experimental parameters.

Traumatic brain injury (TBI) has become a recent focus of biomedical research with a growing international effort targeting material characterization of brain tissue and simulations of trauma using computer models of the head and brain to try to elucidate the mechanisms and pathogenesis of TBI. The meninges, a collagenous protective tri-layer, which encloses the entire brain and spinal cord has been largely overlooked in these material characterization studies. This has resulted in a lack of accurate constitutive data for the cranial meninges, particularly under dynamic conditions such as those experienced during head impacts. The work presented here addresses this lack of data by providing for the first time, in situ large deformation material properties of the porcine dura-arachnoid mater composite under dynamic indentation. It is demonstrated that this tissue is substantially stiffer (shear modulus, μ=19.10±8.55kPa) and relaxes at a slower rate (τ 1 =0.034±0.008s, τ 2 =0.336±0.077s) than the underlying brain tissue (μ=6.97±2.26kPa, τ 1 =0.021±0.007s, τ 2 =0.199±0.036s), reducing the magnitudes of stress by 250% and 65% for strains that arise during indentation-type deformations in adolescent brains., Statement of Significance: We present the first mechanical analysis of the protective capacity of the cranial meninges using in situ micro-indentation techniques. Force-relaxation tests are performed on in situ meninges and cortex tissue, under large strain dynamic micro-indentation. A quasi-linear viscoelastic model is used subsequently, providing time-dependent mechanical properties of these neural tissues under loading conditions comparable to what is experienced in TBI. The reported data highlights the large differences in mechanical properties between these two tissues. Finite element simulations of the indentation experiments are also performed to investigate the protective capacity of the meninges. These simulations show that the meninges protect the underlying brain tissue by reducing the overall magnitude of stress by 250% and up to 65% for strains., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The brain is a complex organ made up of many different functional and structural regions consisting of different types of cells such as neurons and glia, as well as complex anatomical geometries. It is hypothesized that the different regions of the brain exhibit significantly different mechanical properties which may be attributed to the diversity of cells within individual brain regions. The regional viscoelastic properties of P56 mouse brain tissue, up to 70μm displacement, are presented and discussed in the context of traumatic brain injury, particularly how the different regions of the brain respond to mechanical loads. Force-relaxation data obtained from micro-indentation measurements were fit to both linear and quasi-linear viscoelastic models to determine the time and frequency domain viscoelastic response of the pons, cortex, medulla oblongata, cerebellum, and thalamus. The damping ratio of each region was also determined. Each region was found to have a unique mechanical response to the applied displacement, with the pons and thalamus exhibiting the largest and smallest force-response, respectively. All brain regions appear to have an optimal frequency for the dissipation of energies which lies between 1 and 10Hz., Statement of Significance: We present the first mechanical characterization of the viscoelastic response for different regions of mouse brain. Force-relaxation tests are performed under large strain dynamic micro-indentation, and viscoelastic models are used subsequently, providing time-dependent mechanical properties of brain tissue under loading conditions comparable to what is experienced in TBI. The unique mechanical properties of different brain regions are highlighted, with substantial variations in the viscoelastic properties and damping ratio of each region. Cortex and pons were the stiffest regions, while the thalamus and medulla were most compliant. The cerebellum and thalamus had highest damping ratio values and those of the medulla were lowest. The reported material parameters can be implemented into finite element computer models of the mouse to investigate the effects of trauma on individual brain regions., (Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Multiple Sclerosis lesions influence the process of image analysis, leading to tissue segmentation problems and biased morphometric estimates. With the aim of reducing this bias, existing techniques fill segmented lesions as normal appearing white matter. However, due to lesion segmentation errors or the presence of neighbouring structures, such as the ventricles and deep grey matter structures, filling all lesions as white matter like intensities is prone to introduce errors and artefacts. In this paper, we present a novel lesion filling strategy based on in-painting techniques for image completion. This technique makes use of a patch-based Non-Local Means algorithm that fills the lesions with the most plausible texture, rather than normal appearing white matter. We demonstrate that this strategy introduces less bias and fewer artefacts and spurious edges than previous techniques. The advantages of the proposed methodology are that it preserves both anatomical structure and signal-to-noise characteristics even when the lesions are neighbouring grey matter and cerebrospinal fluid, and avoids excess blurring or rasterisation due to the choice of segmentation plane, and lesion shape, size and/or position.

Background: In a phase 2b study in patients with relapsing-remitting MS (RRMS), BG-12 240 mg three times daily significantly reduced the number of new gadolinium-enhanced (Gd+) lesions from weeks 12 to 24 (primary end point) by 69% compared with placebo., Objective: In this analysis, the effect of BG-12 240 mg three times daily on the number of Gd+ lesions from weeks 12 to 24 was evaluated in subgroups based on baseline disease characteristics and demographics., Methods: Two hundred and fifty-seven patients were randomized equally to receive BG-12 (120 mg once daily or three times daily or 240 mg three times daily) or placebo., Results: BG-12 240 mg three times daily significantly reduced the number of new Gd+ lesions compared with placebo in the following subgroups: Expanded Disability Status Scale (EDSS) score ≤ 2.5 (74%), EDSS score > 2.5 (63%), no Gd+ lesions (80%), ≥ 1 Gd+ lesion (55%), age < 40 years (49%), age ≥ 40 years (89%), female patients (81%), disease duration ≤ 6 years (81%) and disease duration > 6 years (54%) (all comparisons p < 0.05)., Conclusion: BG-12 demonstrated efficacy in patients with RRMS by decreasing new Gd+ lesion development across a range of subgroups defined by baseline disease characteristics or demographics.