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Several controlled studies provide evidence that treatment with interferon beta in patients with a first event suggestive of multiple sclerosis (MS) delays conversion to clinically definite MS (CDMS). Our aim was to determine whether early initiation of treatment with interferon beta prevents development of confirmed disability in MS. In the initial placebo-controlled phase of the double-blinded BENEFIT study, patients with a first event suggestive of MS and a minimum of two clinically silent lesions in MRI were randomised to receive either interferon beta-1b 250 μg (n=292) or placebo (n=176) subcutaneously every other day for 2 years, or until diagnosis of CDMS. Patients were then eligible to enter the follow-up phase with open-label interferon beta-1b. In the current prospectively planned analysis 3 years after randomisation, the effects of early interferon beta-1b treatment were compared with those of delayed treatment initiated after diagnosis of CDMS or after 2 years on the study. The primary outcomes of this ITT analysis were time to diagnosis of CDMS, time to confirmed expanded disability status scale (EDSS) progression, and score on a patient-reported functional assessment scale (FAMS-TOI). This trial is registered with ClinicalTrials.gov, number NCT00185211. Of the 468 patients originally randomised, 418 (89%) entered the follow-up phase; 392 (84%) completed 3 years' post-randomisation follow-up. After 3 years, 99 (37%) patients in the early group developed CDMS compared with 85 (51%) patients in the delayed treatment group. Early treatment reduced the risk of CDMS by 41% (hazard ratio 0·59, 95% CI 0·44–0·80; p=0·0011; absolute risk reduction 14%) compared with delayed treatment. Over 3 years, 42 (16%) patients in the early group and 40 (24%) in the delayed group had confirmed EDSS progression; early treatment reduced the risk for progression of disability by 40% compared with delayed treatment (0·60, 0·39–0·92; p=0·022; absolute risk reduction 8%). The FAMS-TOI score was high and stable in both groups over the 3-year period (p=0·31). Our data suggest that early initiation of treatment with interferon beta-1b prevents the development of confirmed disability, supporting its use after the first manifestation of relapsing-remitting MS.

To investigate the prevalence of depressive symptoms in rheumatoid arthritis (RA) patients using two previously validated questionnaires in a large patient sample, and to evaluate depressive symptoms in the context of clinical characteristics (e.g. remission of disease) and patient-reported impact of disease. In this cross-sectional study, the previously validated Patient Health Questionnaire (PHQ-9) and Beck-Depression Inventory II (BDI-II) were used to assess the extent of depressive symptoms in RA patients. Demographic background, RA disease activity score (DAS28), RA impact of disease (RAID) score, comorbidities, anti-rheumatic therapy and antidepressive treatment, were recorded. Cut-off values for depressive symptomatology were PHQ-9 ≥5 or BDI-II ≥14 for mild depressive symptoms or worse and PHQ-9 ≥ 10 or BDI-II ≥ 20 for moderate depressive symptoms or worse. Prevalence of depressive symptomatology was derived by frequency analysis while factors independently associated with depressive symptomatology were investigated by using multiple logistic regression analyses. Ethics committee approval was obtained, and all patients provided written informed consent before participation. In 1004 RA-patients (75.1% female, mean±SD age: 61.0±12.9 years, mean disease duration: 12.2±9.9 years, DAS28 (ESR): 2.5±1.2), the prevalence of depressive symptoms was 55.4% (mild or worse) and 22.8% (moderate or worse). Characteristics independently associated with depressive symptomatology were: age <60 years (OR = 1.78), RAID score >2 (OR = 10.54) and presence of chronic pain (OR = 3.25). Of patients classified as having depressive symptoms, only 11.7% were receiving anti-depressive therapy. Mild and moderate depressive symptoms were common in RA patients according to validated tools. In routine clinical practice, screening for depression with corresponding follow-up procedures is as relevant as incorporating these results with patient-reported outcomes (e.g. symptom state), because the mere assessment of clinical disease activity does not sufficiently reflect the prevalence of depressive symptoms. This study is registered in the Deutsches Register Klinischer Studien (DRKS00003231) and ClinicalTrials.gov (NCT02485483).

The Betaferon/Betaseron in newly emerging multiple sclerosis for initial treatment (BENEFIT) trial investigated the effect of treatment with interferon beta-1b after a clinically isolated syndrome. The 5-year active treatment extension compares the effects of early and delayed treatment with interferon beta-1b on time to clinically definite multiple sclerosis (CDMS) and other disease outcomes, including disability progression. Patients with a first event suggestive of multiple sclerosis and a minimum of two clinically silent lesions in MRI were randomly assigned to receive interferon beta-1b 250 μg (n=292; early treatment) or placebo (n=176; delayed treatment) subcutaneously every other day for 2 years, or until diagnosis of CDMS. All patients were then eligible to enter a prospectively planned follow-up phase with open-label interferon beta-1b up to a maximum of 5 years after randomisation. Patients and study personnel remained unaware of initial treatment allocation throughout the study. Primary endpoints were time to CDMS, time to confirmed disability progression measured with the expanded disability status scale, and the functional assessment of multiple sclerosis trial outcomes index (FAMS-TOI) at 5 years. Analysis of the primary endpoints was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00185211. 235 (80%) patients from the early treatment and 123 (70%) from the delayed treatment group completed the 5-year study. Early treatment reduced the risk of CDMS by 37% (hazard ratio [HR] 0·63, 95% CI 0·48–0·83; p=0·003) compared with delayed treatment. The risk for confirmed disability progression was not significantly lower in the early treatment group (0·76, 0·52–1·11; p=0·177). At 5 years, median FAMS-TOI scores were 125 in both groups. No significant differences in other disability related outcomes were recorded. Frequency and severity of adverse events remained within the established safety and tolerability profile of interferon beta-1b. Effects on the rate of conversion to CDMS and the favourable long-term safety and tolerability profile support early initiation of treatment with interferon beta-1b, although a delay in treatment by up to 2 years did not affect long-term disability outcomes. Bayer Schering Pharma.

The aim of the Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) trial was to compare the efficacy, safety, and tolerability of 250 μg or 500 μg interferon beta-1b with glatiramer acetate for treating relapsing-remitting multiple sclerosis. Between November, 2003, and June, 2005, 2447 patients with relapsing-remitting multiple sclerosis were screened and 2244 patients were enrolled in this prospective, multicentre, randomised trial. Patients were randomly assigned 2:2:1 by block randomisation with regional stratification to receive one of two doses of interferon beta-1b (250 μg or 500 μg) subcutaneously every other day or 20 mg glatiramer acetate subcutaneously every day. The primary outcome was relapse risk, defined as new or recurrent neurological symptoms separated by at least 30 days from the preceding event and that lasted at least 24 h. Secondary outcomes were progression on the expanded disability status scale (EDSS) and change in T1-hypointense lesion volume. Clinical outcomes were assessed quarterly for 2·0–3·5 years; MRI was done at screening and annually thereafter. Analysis was by per protocol. This study is registered, number NCT00099502. We found no differences in relapse risk, EDSS progression, T1-hypointense lesion volume, or normalised brain volume among treatment groups. Flu-like symptoms were more common in patients treated with interferon beta-1b (p<0·0001), whereas injection-site reactions were more common in patients treated with glatiramer acetate (p=0·0005). Patient attrition rates were 17% (153 of 888) on 250 μg interferon beta-1b, 26% (227 of 887) on 500 μg interferon beta-1b, and 21% (93 of 445) for glatiramer acetate. 500 μg interferon beta-1b was not more effective than the standard 250 μg dose, and both doses had similar clinical effects to glatiramer acetate. Although interferon beta-1b and glatiramer acetate had different adverse event profiles, the overall tolerability to both drugs was similar. Bayer HealthCare Pharmaceuticals.

Prediction of susceptibility to multiple sclerosis (MS) might have important clinical applications, either as part of a diagnostic algorithm or as a means to identify high-risk individuals for prospective studies. We investigated the usefulness of an aggregate measure of risk of MS that is based on genetic susceptibility loci. We also assessed the added effect of environmental risk factors that are associated with susceptibility for MS. We created a weighted genetic risk score (wGRS) that includes 16 MS susceptibility loci. We tested our model with data from 2215 individuals with MS and 2189 controls (derivation samples), a validation set of 1340 individuals with MS and 1109 controls taken from several MS therapeutic trials (TT cohort), and a second validation set of 143 individuals with MS and 281 controls from the US Nurses' Health Studies I and II (NHS/NHS II), for whom we also have data on smoking and immune response to Epstein-Barr virus (EBV). Individuals with a wGRS that was more than 1·25 SD from the mean had a significantly higher odds of MS in all datasets. In the derivation sample, the mean (SD) wGRS was 3·5 (0·7) for individuals with MS and 3·0 (0·6) for controls (p<0·0001); in the TT validation sample, the mean wGRS was 3·4 (0·7) for individuals with MS versus 3·1 (0·7) for controls (p<0·0001); and in the NHS/NHS II dataset, the mean wGRS was 3·4 (0·8) for individuals with MS versus 3·0 (0·7) for controls (p<0·0001). In the derivation cohort, the area under the receiver operating characteristic curve (C statistic; a measure of the ability of a model to discriminate between individuals with MS and controls) for the genetic-only model was 0·70 and for the genetics plus sex model was 0·74 (p<0·0001). In the TT and NHS cohorts, the C statistics for the genetic-only model were both 0·64; adding sex to the TT model increased the C statistic to 0·72 (p<0·0001), whereas adding smoking and immune response to EBV to the NHS model increased the C statistic to 0·68 (p=0·02). However, the wGRS does not seem to be correlated with the conversion of clinically isolated syndrome to MS. The inclusion of 16 susceptibility alleles into a wGRS can modestly predict MS risk, shows consistent discriminatory ability in independent samples, and is enhanced by the inclusion of non-genetic risk factors into the algorithm. Future iterations of the wGRS might therefore make a contribution to algorithms that can predict a diagnosis of MS in a clinical or research setting. National MS Society.

A previous study reported in the Journal showed an association between serum antimyelin antibodies (detected by Western blot analysis) and an increased risk of multiple sclerosis in patients with the first evidence of neurologic abnormalities that were suggestive, but not diagnostic, of multiple sclerosis. This prospective study of 462 patients did not reproduce these findings but instead showed that serum antibodies against myelin oligodendrocyte glycoprotein and myelin basic protein were not associated with an increased risk of progression to clinically definite multiple sclerosis. Serum antibodies against myelin oligodendrocyte glycoprotein and myelin basic protein were not associated with an increased risk of progression to clinically definite multiple sclerosis. After a first episode of central nervous system dysfunction that is suggestive of multiple sclerosis (known as a clinically isolated syndrome), it is difficult to predict the individual risk of multiple sclerosis. Berger et al. 1 reported a significantly increased risk of clinically definite multiple sclerosis among patients with a clinically isolated syndrome and serum antibodies against recombinant myelin oligodendrocyte glycoprotein (MOG) and purified myelin basic protein (MBP), detected by Western blot analysis. MOG is a minor component of myelin (0.01 to 0.05% of central myelin protein) that is found exclusively in the central nervous system. 2 The N-terminal domain of MOG . . .

The present article gives an overview of the first experimental campaigns carried out in the AKR-2 and CROCUS reactors within the framework of the Horizon 2020 European project CORTEX. CORTEX aims at developing innovative core monitoring techniques that allow detecting anomalies in nuclear reactors, e.g. excessive vibrations of core internals. The technique will be mainly based on using the fluctuations in neutron flux, i.e. noise analysis. The project will result in a deepened understanding of the physical processes involved. This will allow utilities to detect operational problems at a very early stage, and to take proper actions before such problems have any adverse effect on plant safety and reliability. The purpose of the experimental campaigns in the AKR-2 and CROCUS reactors is to produce noise-specific experimental data for the validation of the neutron noise computational models developed within this framework. The first campaigns at both facilities consisted in measurements at reference static states, and with the addition of mechanical perturbations. In the AKR-2 reactor, perturbations were induced by two devices: a rotating absorber and a vibrating absorber, both sets in experimental channels close to the core. In CROCUS, the project benefited from the COLIBRI experimental program: 18 periphery fuel rods were oscillated at a maximum of ±2 mm around their central position in the Hz range. The present article documents the experimental setups and measurements for each facility and perturbation type.

To assess, from a Swedish societal perspective, the cost effectiveness of interferon β-1b (IFNB-1b) after an initial clinical event suggestive of multiple sclerosis (MS) (ie, early treatment) compared with treatment after onset of clinically definite MS (CDMS) (ie, delayed treatment). A Markov model was developed, using patient level data from the BENEFIT trial and published literature, to estimate health outcomes and costs associated with IFNB-1b for hypothetical cohorts of patients after an initial clinical event suggestive of MS. Health states were defined by Kurtzke Expanded Disability Status Scale (EDSS) scores. Model outcomes included quality-adjusted life years (QALYs), total costs (including both direct and indirect costs), and incremental cost-effectiveness ratios. Sensitivity analyses were performed on key model parameters to assess the robustness of model results. In the base case scenario, early IFNB-1b treatment was economically dominant (ie, less costly and more effective) versus delayed IFNB-1b treatment when QALYs were used as the effectiveness metric. Sensitivity analyses showed that the cost-effectiveness results were sensitive to model time horizon. Compared with the delayed treatment strategy, early treatment of MS was also associated with delayed EDSS progressions, prolonged time to CDMS diagnosis, and a reduction in frequency of relapse. Early treatment with IFNB-1b for a first clinical event suggestive of MS was found to improve patient outcomes while controlling costs.

Transport vlhkosti uvnitř betonu při zvýšených teplotách je klíčovým faktorem pro pochopení rizika odstřelování betonu (spalling). Třífázový model (pevná fáze, suchý vzduch, voda) řeší bilanční rovnice pro pevnou fázi, suchý vzduch, vodní páru, kapalnou vodu a entalpii pomocí metody konečných prvků. Model byl napsán v prostředí FEniCS a řeší dříve opomíjenou bilanci hmotnosti skeletu zavedením pórovitosti jako další nezávislé proměnné. Kromě splnění hmotnostní bilance to umožňuje řešit o jednu konstitutivní rovnici méně a snadnější validaci.Model byl experimentálně ověřen daty z 3D rentgenové počítačové tomografie (CT). Byla provedena kvantifikace nejistoty pro informovanější rozhodnutí o věrohodnosti modelu. Byly identifikovány odchylky ve vstupních parametrech, prostor parametrů byl nasamplován pomocí metody LHS a určeny výsledné variace na výstupu.Numerický vícefázový model umožňuje predikci obsahu vody a tlaků uvnitř pórů. Řešení bilance hmotnosti skeletu vede k realističtějším hodnotám než vykazovaly předchozí modely. Model ukázal, že popis dehydratace založené pouze na termogravimetrické analýze nemůže vysvětlit pozorovanou změnu vlhkosti v datech CT. Kvantifikace nejistoty ukazuje variační součinitel mezi 12 % a 16 % pro maximální tlak plynu a jeho pozici, jako důležité indikátory pro vznik odstřelování betonu. Maximální tlak plynu dosahuje přibližně 7,5 MPa a vyskytuje se 50 mm až 100 mm od exponovaného povrchu. Takové zjištění je v souladu s experimenty odstřelování betonu.

Background Interferon-beta (IFNB) therapy for multiple sclerosis can lead to the induction of neutralizing antibodies (NAbs) against IFNB. Various methods are used for detection and quantification of NAbs. Methods Blood samples from 125 IFNB-1b–treated patients, which were tested NAb negative or NAb positive after conclusion of a clinical study, were retested three years after first being assessed in four different laboratories that offer routine NAb testing to practicing neurologists. The myxovirus protein A (MxA) induction assay, the cytopathic effect (CPE) assay (two laboratories), or the luciferase assay were used. Intra- and inter-laboratory agreement between assays with respect to NAb detection and NAb titer quantification were evaluated. Results High agreement for NAb detection (kappa coefficient, 0.86) and for titer levels was observed for the intra-laboratory comparison in the laboratory using the MxA induction assay performed three years ago and now. A similarly high agreement for NAb detection (kappa coefficient, 0.87) and for titer quantification was noted for the MxA assay of this laboratory with one of two laboratories using the CPE assay. All other inter-laboratory comparisons showed kappa values between 0.57 and 0.68 and remarkable differences in individual titer levels. Conclusions There are considerable differences in the detection and quantification of IFNB-induced NAbs among laboratories offering NAb testing for clinical practice using different assay methods. It is important that these differences are considered when interpreting NAb results for clinical decision-making and when developing general recommendations for potentially clinically meaningful NAb titer levels.