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ObjectiveTo 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).MethodsMagnetic 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.ResultsBaseline 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

This paper presents a numerical investigation of the effect of wing integration on the aerodynamic behavior of a typical large civil aero-engine exhaust system at wind-milling flow conditions. The work is based on the dual stream jet propulsion (DSJP) test rig, as will be tested within the transonic wind tunnel (TWT) located at the aircraft research association (ARA) in the UK. The DSJP rig was designed to measure the impact of the installed pressure field due to the effect of the wing on the aerodynamic performance of separate-jet exhausts. The rig is equipped with the dual separate flow reference nozzle (DSFRN), installed under a swept wing. Computational fluid dynamic simulations were carried out for representative ranges of fan and core nozzle pressure ratios (CNPR) for "engine-out" wind-milling scenarios at end of runway (EOR) takeoff, diversion, and cruise conditions. Analyses were done for both isolated and installed configurations to quantify the impact of the installed pressure field on the fan and core nozzle discharge coefficients. The impact of fan and core nozzle pressure ratios, as well as freestream Mach number and high-lift surfaces on the installed suppression effect, was also evaluated. It is shown that the installed pressure field can reduce the fan nozzle discharge coefficient by up to 16%, relative to the isolated configuration for EOR wind-milling conditions. The results were used to inform the design and setup of the experimental activity which is planned for 2023. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate the effects of oral delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) on MRI lesion activity and load, atrophy, and magnetization transfer ratio (MTR) measures from the Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (CONFIRM) study. METHODS: CONFIRM was a 2-year, placebo-controlled study of the efficacy and safety of DMF 240 mg twice (BID) or 3 times daily (TID) in 1,417 patients with relapsing-remitting multiple sclerosis (RRMS); subcutaneous glatiramer acetate 20 mg once daily was included as an active reference comparator. The number and volume of T2-hyperintense, T1-hypointense, and gadolinium-enhancing (Gd+) lesions, as well as whole brain volume and MTR, were assessed in 681 patients (MRI cohort). RESULTS: DMF BID and TID produced significant and consistent reductions vs placebo in the number of new or enlarging T2-hyperintense lesions and new nonenhancing T1-hypointense lesions after 1 and 2 years of treatment and in the number of Gd+ lesions at week 24, year 1, and year 2. Lesion volumes were also significantly reduced. Reductions in brain atrophy and MTR changes with DMF relative to placebo did not reach statistical significance. CONCLUSIONS: The robust effects on MRI active lesion counts and total lesion volume in patients with RRMS demonstrate the ability of DMF to exert beneficial effects on inflammatory lesion activity in multiple sclerosis, and support DMF therapy as a valuable new treatment option in RRMS. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence of reduction in brain lesion number and volume, as assessed by MRI, over 2 years of delayed-release DMF treatment.

Background: 1H‐magnetic resonance spectroscopy (1H‐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 1H‐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: 1H‐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 [ABSTRACT FROM AUTHOR]