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Background: Occipital strokes often cause permanent homonymous hemianopia leading to significant disability. In previous studies, non-invasive electrical brain stimulation (NIBS) has improved vision after optic nerve damage and in combination with training after stroke. Objective: We explored different NIBS modalities for rehabilitation of hemianopia after chronic stroke. Methods: In a randomized, double-blinded, sham-controlled, three-armed trial, altogether 56 patients with homonymous hemianopia were recruited. The three experiments were: i) repetitive transorbital alternating current stimulation (rtACS, n = 8) vs. rtACS with prior cathodal transcranial direct current stimulation over the intact visual cortex (tDCS/rtACS, n = 8) vs. sham (n = 8); ii) rtACS (n = 9) vs. sham (n = 9); and iii) tDCS of the visual cortex (n = 7) vs. sham (n = 7). Visual functions were evaluated before and after the intervention, and after eight weeks follow-up. The primary outcome was change in visual field assessed by high-resolution and standard perimetries. The individual modalities were compared within each experimental arm. Results: Primary outcomes in Experiments 1 and 2 were negative. Only significant between-group change was observed in Experiment 3, where tDCS increased visual field of the contralesional eye compared to sham. tDCS/rtACS improved dynamic vision, reading, and visual field of the contralesional eye, but was not superior to other groups. rtACS alone increased foveal sensitivity, but was otherwise ineffective. All trial-related procedures were tolerated well. Conclusions: This exploratory trial showed safety but no main effect of NIBS on vision restoration after stroke. However, tDCS and combined tDCS/rtACS induced improvements in visually guided performance that need to be confirmed in larger-sample trials. NCT01418820 (clinicaltrials.gov)

In pandemic crises such as the COVID-19 pandemic, individuals’ behavior has a strong impact on epidemiological processes. Compliance with prevention guidelines, such as social distancing, is critical to avoid further spreading an infectious disease or to slow down its spread. However, some individuals also or instead engage in panic behavior, such as hoarding. We investigate how education prepares individuals to respond adequately by modelling the path from seeking information about COVID-19 to eventual behavior. Based on a sample of N = 1182 adult Americans, gathered at the pandemic’s onset (March 2020), we conclude that science knowledge helps individuals convert information into coronavirus knowledge. This knowledge then helps individuals avoid panic behavior. Individuals lacking coronavirus knowledge and science knowledge still comply with prevention guidelines when they have a general trust in medicine. Individuals lacking knowledge still follow prevention guidelines when they trust in medicine. Facilitating science knowledge and trust in science through education and targeted public health messaging are likely to be of fundamental importance for bringing crises such as the COVID-19 pandemic under control.

Eine 40-jahrige Patientin stellt sich in der hausarztlichen Sprechstunde vor. Mit besorgter Miene berichtet sie uber seit sechs Monaten anhaltende allgemeine Schwache und Schweisausbruche. Die Symptomatik hatte sich in den letzten Tagen verstarkt. Sie habe grose Angst, an einer schweren Erkrankung zu leiden.

A brief survey among members of the German Neurorehabilitation Society aimed to document the hospital capacities (“beds”) for prolonged weaning from a mechanical ventilator for patients with neuro-disabilities that require simultaneous multi-professional neurorehabilitation treatment. Sixty-eight institutions declared to have capacities with a broad distribution across Germany and its federal states. Overall, 1094 “beds” for prolonged weaning (and neurorehabilitation) were reported, 871 together with further information regarding their identification and hence regional location. These units had on average 16.1 beds for prolonged weaning (95% confidence interval 12.6 to 19.6) with a range from 2 to 68 beds per organization. The data indicate substantial capacities for the combined prolonged weaning and neurorehabilitation treatment in Germany. For most “beds” included in this analysis a basic validation was possible. While a reasonable coverage of these specialized service capacities by the survey is likely, the number reported could still be biased by underreporting by non-response. Both the broad variation of number of “beds” for prolonged weaning per unit and their unequal geographical distribution across federal states (per capita rate) warrant a more refined follow-up survey that will provide insights into reasons for the observed pattern of variation for these specialized hospital capacities.

Functional electrical stimulation and robot-assisted gait training are techniques which are used in a clinical routine to enhance the rehabilitation process of stroke patients. By combining these technologies, therapy effects could be further improved and the rehabilitation process can be supported. In order to combine these technologies, a novel algorithm was developed, which aims to extract gait events based on movement data recorded with inertial measurement units. In perspective, the extracted gait events can be used to trigger functional electrical stimulation during robot-assisted gait training. This approach offers the possibility of equipping a broad range of potential robot-assisted gait trainers with functional electrical stimulation. In particular, the aim of this study was to test the robustness of the previously developed algorithm in a clinical setting with patients who suffered a stroke. A total amount of N = 10 stroke patients participated in the study, with written consent. The patients were assigned to two different robot-assisted gait trainers (Lyra and Lokomat) according to their performance level, resulting in five recording sessions for each gait-trainer. A previously developed algorithm was applied and further optimized in order to extract the gait events. A mean detection rate across all patients of 95.8% ± 7.5% for the Lyra and 98.7% ± 2.6% for the Lokomat was achieved. The mean type 1 error across all patients was 1.0% ± 2.0% for the Lyra and 0.9% ± 2.3% for the Lokomat. As a result, the developed algorithm was robust against patient specific movements, and provided promising results for the further development of a technique that can detect gait events during robot-assisted gait training, with the future aim to trigger functional electrical stimulation.

We propose a model of contextual facilitators for learning activities involving technology (in short: C♭-model) for both on-site and distance learning environments in higher education. The C♭-model aims at systematizing research on digital teaching and learning and offers a roadmap for future research to understand the complex dynamic of factors that lead to successful digital teaching and learning in higher education via suitable learning activities. First, we introduce students' learning outcomes as central benchmarks of teaching and learning with digital technologies in higher education. Second, we want to focus on a major proximal factor for students' learning outcomes and thus apply a learning activities perspective. Learning activities involving digital technologies reflect cognitive processes of students when using digital technologies and are causally connected with students' learning outcomes. Third, we highlight several contextual facilitators for learning activities involving technology in the C♭-model: learning opportunities that result from higher education teachers' instructional use of technology and students' self-arranged learning opportunities involving digital technologies. Apart from these proximal facilitators, we include more distal factors, namely, higher education teachers' knowledge, skills, and attitudes toward digital technology; higher education teachers' qualification; students' and teachers’ digital technology equipment; and institutional, organizational, and administrative factors.

Background Memory impairment (MI) is a common symptom of MS. Previous studies were conflicting in respect to the possible existence of early MI and the role of hippocampal atrophy. The objective of this study was to investigate MI and structural MRI correlates in homogenous groups of early and late MS, controlling for a potential information-processing speed (IPS) deficit, and utilizing multiple memory test paradigms. Methods 152 individually matched subjects were recruited: early MS (EMS, N = 25, disease duration 1.0 ± 0.8 years), late MS (LMS, N = 52, 16.5 ± 5.2 years), and corresponding controls. Five memory tests were utilized to account for differences in learning material (verbal, visual), encoding (incidental, intentional), and retrieval (free recall, recognition, recurring recognition). Performance was related to IPS, memory-specific (hippocampal volumes), and unspecific MRI measures (T1/T2LL, brain volume, cortical thickness). Results Memory was impaired across all tests in LMS, but not in EMS. LMS-patients were also significantly impaired in IPS which was correlated with several memory scores. Regression analyses revealed IPS and cortical thickness as predictors for visual MI, and IPS, sex, and left hippocampal volume as predictors for verbal MI. Conclusion Additionally to direct destructions in memory specific tracts such as the hippocampus, memory decline in MS may also be related to a general factor comprising slowed information-processing and global tissue loss.

ZusammenfassungEine standardisierte Therapie der oberen Extremität bei Patienten mit einer Störung des zentralen Nervensystems (ZNS) liegt bisher nicht vor. In der letzten Dekade hat die roboter- und gerätegestützte Therapie die Behandlung der motorischen Funktionsstörungen der oberen Extremität nach Schlaganfall in der Neurorehabilitation deutlich beeinflusst. Die vorliegende Arbeit gibt einen Überblick zu den technischen Grundlagen und zur Differenzierung der verschiedenen Gerätetypen. Unter Einbeziehung ausgewählter Studien wird die Praxis der roboter- und gerätegestützten Rehabilitation der oberen Extremität dargestellt. Die Effektivität der gerätegestützten Therapie der oberen Extremität ist, im Vergleich zu einer gleichwertig intensiven konventionellen Therapie, weiterhin diskutabel, nicht zuletzt auch aufgrund der recht heterogenen Studienlage. Dennoch weisen die Entwicklung und der Einsatz roboter- und gerätegestützter Therapieformen der oberen Extremität in eine vielversprechende Zukunft. Sie können das Personal entlasten und stellen aktuell eine sinnvolle Ergänzung zur konventionellen Therapie dar.

Neurorehabilitation of patients with upper limb motor dysfunction due to central nervous system damage still lacks adequate standardization. During the last decade, robot- and device-assisted rehabilitation has become more feasible for the treatment of functional disorders of the upper limb after stroke. Here we present an overview of technological aspects and differential use of devices for upper limb rehabilitation as well as a review of relevant clinical studies. We also discuss the potential for standardized evaluation in the context of limited health care resources. The effectiveness of device-assisted therapy, in comparison to conventional approaches, remains a matter of debate, largely due to the heterogeneous design of the available clinical studies. However, we believe that a better understanding of the timing, intensity, and quality of upper limb rehabilitation, as well as technological progress, will lead to the establishment of a central role for robot- and device-assisted rehabilitation in the next decade.

Motor recovery following stroke is believed to necessitate alteration in functional connectivity between cortex and muscle. Cortico-muscular coherence has been proposed as a potential biomarker for post-stroke motor deficits, enabling a quantification of recovery, as well as potentially indicating the regions of cortex involved in recovery of function. We recorded simultaneous EEG and EMG during wrist extension from healthy participants and patients following ischaemic stroke, evaluating function at three time points post-stroke. EEG–EMG coherence increased over time, as wrist mobility recovered clinically, and by the final evaluation, coherence was higher in the patient group than in the healthy controls. Moreover, the cortical distribution differed between the groups, with coherence involving larger and more bilaterally scattered areas of cortex in the patients than in the healthy participants. The findings suggest that EEG–EMG coherence has the potential to serve as a biomarker for motor recovery and to provide information about the cortical regions that should be targeted in rehabilitation therapies based on real-time EEG.

This study investigated the initiation of digitally supported learning activities and personal and institutional factors associated with them in different higher education courses, based on the C♭-model. The C♭-model is a theoretical framework that systematizes contextual factors, which influence students‘ learning activities as the most important facilitator of students’ learning success. Using a self-assessment instrument with anchored scenarios in a sample of 1625 higher education teachers, we were able to identify three levels at which higher education teachers initiated digital learning activities: a low level (powerpointers), a moderate level (clickerers), and a high level (digital pros). The findings also support the relevance of the contextual factors specified in the C♭-model for initiating a high level of digital learning activities, namely digitalization policy and commitment of university administration, institutional equipment, technical and educational support, self-assessed basic digital skills, and self-assessed technology-related teaching skills. All of these factors explain a substantial amount of variance in the level of initiated digital learning activities. We conclude that a comprehensive approach rather than isolated measures might contribute to successful teaching and learning in higher education.

This is the introductory article for the special issue “Technology-related knowledge, skills, and attitudes of pre- and in-service teachers”. It (1) specifies the concept of technology-related knowledge, skills, and attitudes (KSA) of teachers, (2) presents how these KSA are currently assessed, and (3) outlines ways of fostering them among pre- and in-service teachers. The eight articles in the special issue are structured accordingly, and we demonstrate how they contribute to knowledge in these three areas. Moreover, we show how the afterword to the special issue widens the perspective on technology integration by taking into account systems and cultures of practice. Due to their quantitative empirical nature, the eight articles investigate technology at the current state of the art. However, the potential of artificial intelligence has not yet been fully exploited in education. We provide an outlook on potential developments and their implications on teachers’ technology-related KSA. To this end, we introduce the concept of augmentation strategies., Highlights • Review of teachers' technology related knowledge, skills, and attitudes (KSA). • Three areas: specification, assessment, and ways of fostering. • Explanation of contribution of the eight articles in the special issue. • Outlook on KSA changes due to technological developments: artificial intelligence.

Research in social sciences and humanities of ten involves analysing data to draw scientific conclusions. This however requires the manual coding of the data, which is highly time-consuming. A use case is the coding of students' essays in education to draw conclusions about students' reasoning and argumentation. The NeuralWeb API tackles this problem by providing automatic codings to other software components. These codings can for example be used in annotation platforms in terms of recommendations for expert coders from social sciences and humanities. After some initial manual annotations, the expert coders then merely need to verify the correctness of the automatic codings instead of manually annotating all data.

Although there are several empirical studies about active learning in higher education, there are some open research questions. Especially, it appears to be relevant to find out what type of activity (active, interactive and constructive) has a positive effect on the learning result of participants in task-based activities. In order to answer this question an experimental study was conducted with students in German higher education (N=50). The results do not show a significant difference between active, interactive and constructive activities on learning performance in task-based learning. But all groups have benefited from the classroom activities according to the test results.

Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance.

Multiple Sklerose (MS) ist eine entzundliche Erkrankung des zentralen Nervensystems, die einen axonal-destruktiven Anteil aufweist, der masgeblich die Behinderung im Laufe der Erkrankung bestimmt. In den letzten 3 Dekaden etablierte sich die Magnetresonanztomografie (MRT) zum wichtigsten Verfahren in der Diagnosestellung der MS. Die hohe Sensitivitat der konventionellen MRT erlaubt die In-vivo-Detektion von fokalen und diffusen entzundlichen Komponenten dieser Erkrankung. Der Nachweis und die Quantifizierung von fokalen Pathologien der in der klinischen Routine eingesetzten MRT tragt entscheidend zur fruhen Diagnose der MS bei. Der Nachweis einer Lasionslast im MRT zu Beginn der Erkrankung erhoht die Wahrscheinlichkeit einer fruhen Konversion zur klinisch definitiven MS und einer hoheren Behinderung in den ersten Jahren der Erkrankung. Dieser diagnostische und prognostische Informationsgewinn zu einem fruhen Zeitpunkt der Erkrankung fuhrte 2001 zu einer grundlegenden Revision der diagnostischen Kriterien. Das Konzept der Diagnosestellung beinhaltet klinische und kernspintomografische Kriterien. Diese zuletzt 2010 revidierten diagnostischen Kriterien weisen das Hauptmerkmal auf, dass eine subklinische kernspintomografische Aktivitat der Erkrankung einen Schub ersetzt. Daruber hinaus kann die Diagnose MS bereits nach dem ersten Schub und einem MRT gestellt werden, vorausgesetzt, es lassen sich kernspintomografische Aktivitatszeichen nachweisen. Die fruhe Diagnosestellung unter Berucksichtigung der MRT eroffnet die Moglichkeit einer fruhzeitigen Behandlung innerhalb eines offenbar gunstigeren therapeutischen Fensters.

Occipital stroke often leads to visual field loss, for which no effective treatment exists. Little is known about the potential of non-invasive electric current stimulation to ameliorate visual functions in patients suffering from unilateral occipital stroke. One reason is the traditional thinking that visual field loss after brain lesions is permanent. Since evidence is available documenting vision restoration by means of vision training or non-invasive electric current stimulation future studies should also consider investigating recovery processes after visual cortical strokes. Here, protocols of repetitive transorbital alternating current stimulation (rtACS) and transcranial direct current stimulation (tDCS) are presented and the European consortium for restoration of vision (REVIS) is introduced. Within the consortium different stimulation approaches will be applied to patients with unilateral occipital strokes resulting in homonymous hemianopic visual field defects. The aim of the study is to evaluate effects of current stimulation of the brain on vision parameters, vision-related quality of life, and physiological parameters that allow concluding about the mechanisms of vision restoration. These include EEG-spectra and coherence measures, and visual evoked potentials. The design of stimulation protocols involves an appropriate sham-stimulation condition and sufficient follow-up periods to test whether the effects are stable. This is the first application of non-invasive current stimulation for vision rehabilitation in stroke-related visual field deficits. Positive results of the trials could have far-reaching implications for clinical practice. The ability of non-invasive electrical current brain stimulation to modulate the activity of neuronal networks may have implications for stroke rehabilitation also in the visual domain.

Objective:We investigated corticospinal tract (CST) integrity in the absence of white matter (WM) lesions using diffusion tensor imaging (DTI) in early MS disease stages.Methods:Our study comprised 19 patients with clinically isolated syndrome (CIS), 11 patients with relapsing-remitting MS (RRMS), and 32 age- and sex-matched healthy controls, for whom MRI measures of CST integrity (fractional anisotropy [FA], mean diffusivity [MD]), T1- and T2-based lesion load, and brain volumes were available. The mean (SD) disease duration was 3.5 (2.1) months, and disability score was low (median Expanded Disability Status Scale 1.5) at the time of the study.Results:Patients with CIS and RRMS had significantly lower CST FA and higher CST MD values compared with controls. These findings were present, irrespective of whether WM lesions affected the CST. However, no group differences in the overall gray or WM volume were identified.Conclusions:In early MS disease stages, CST integrity is already affected in the absence of WM lesions or brain atrophy.

Work competencies can be defined as learned abilities to adequately perform a task, role or mission (Roe 2002). In the workplace context, work-integrated learning approaches are particularly promising approaches for developing work competencies while ensuring transfer and relevance for practice (Sonntag and Stegmaier 2007). However, apart from developing competencies, it is also important that newly acquired competencies are actually applied in the workplace. Hereby motivation plays an essential role. Work environments, which support feelings of competence, autonomy and relatedness, are the foundation for maintaining motivation (Ryan and Deci 2000).

Gamification, as opposed to serious gaming, focuses on the integration of certain elements and mechanics from the field of gaming and game design into an existing (nongaming) environment. Typical game design models do not meet the requirements of implementing a gamification application in total because they focus on the development of a holistic game. An implementation model for the gamification of business processes should focus on the integration of game elements and mechanics into an existing work context instead. An implementation model was designed to fulfill these demands and will be presented in this paper. The so-called GameLog Model can be divided into three major phases: the analysis and exploration phase, the design and realization phase, and the evaluation and reflection phase. Within the analysis and exploration phase, the context that should be gamified is described on a granular level to find integration points for the game elements that do not change the process. In the design and realization phase, the gamification application is developed and implemented in the nongaming context. During the evaluation and reflection phase, the success of the application, as well as the acceptance of the employees, is measured. Results lead to a possible redesign. The model was evaluated by designing and testing a gamification application for the field of material handling. The gamification prototype was created for the process of manual order picking. Significant results could be achieved in fostering motivation and improving performance among workers in this process. Hence, the introduced model does work to successfully implement a gamification application into a business process. Gamification can also be seen as a useful approach to foster motivation and increase the performance of employees.

Objective: The objective of this study was to assess the effect of treatment with interferon (IFN) β-1a, 44 µg subcutaneously (sc) three times weekly (tiw), on clinical and magnetic resonance imaging (MRI) outcomes in patients with relapsing multiple sclerosis (MS) following mitoxantrone therapy. Methods: This was an open-label, randomized, multicentre, rater-blinded, 96-week observational study conducted in Germany. Clinically stable patients with relapsing forms of MS, who had discontinued mitoxantrone treatment 1–6 months before study entry, were randomized to IFN β-1a sc 44 µg tiw, or no treatment. The primary endpoint was time to first relapse. Secondary endpoints included the number of relapse-free patients, disease activity assessed by MRI and time to 3-month confirmed Expanded Disability Status Scale (EDSS) progression, all at week 96. Results: A total of 30 patients were randomized (intent-to-treat population: 14 IFN β-1a, 15 untreated; one patient from the safety population discontinued the study after 25 days owing to an adverse event and without providing any postbaseline efficacy data, and was thus excluded from the intent-to-treat population). Overall, 71.4% (10/14) of patients in the IFN β-1a group remained relapse free over 96 weeks, versus 46.7% (7/15) in the untreated group ( p = 0.26). IFN β-1a delayed the time to first relapse versus no treatment ( p = 0.14); time to first relapse (25th percentile) was 95.4 (IFN β-1a) versus 46.0 weeks (no treatment). Confirmed EDSS progression was observed in five patients in each treatment group. Mean change in EDSS score was 0.3 in both groups ( p = 0.79). Changes in the number or volume of T1 and T2 lesions at week 96 were not significantly different between treatment groups ( p > 0.05). There were no new or unexpected adverse events related to IFN β-1a treatment. Conclusions: Several endpoints appeared to show a benefit of IFN β-1a treatment, but no significant differences could be detected owing to the small sample. Therefore, these data only permit, at best, tentative conclusions about the disease course in patients with MS after de-escalation from mitoxantrone and continuation with or without IFN β-1a. Larger confirmatory studies are required.

Background: Patient-reported quality of life (QOL) is an outcome measure in clinical trials in multiple sclerosis (MS), but translated QOL instruments may affect the actual comparability of data. Objectives: We aimed to investigate possible differences in QOL in MS between cultures and countries. We employed the Functional Assessment of Multiple Sclerosis (FAMS) Version 4 questionnaire, which is a state-of-the-art QOL instrument. Methods: Some 484 MS patients from Austria (145), Germany (144), and Poland (195) aged 20–60 years, and stratified for sex and disease severity as measured by the Expanded Disability Status Scale (EDSS) score completed the respective FAMS translation and a socio-demographic questionnaire. Results: Analysis of variance and post-hoc Scheffé-test showed that 64% of the FAMS items were answered significantly differently ( p Conclusions: Differences exist in the QOL of MS patients from Austria, Germany, and Poland which seem to lie beyond the impact of disease severity. They appear to be related to culture or other country-specific factors, as country was an independent predictor of differently answered items of the FAMS and thus also of the whole FAMS. QOL instruments should consider this aspect to faithfully reflect subjective information such as patient-reported benefit of treatment in multinational clinical trials.

Multiple sclerosis (MS) is an inflammatory disease the central nervous system. Its first manifestation and clinical course of the disease is highly heterogeneous. The diagnosis is based on the verification of neurological deficits, the development of the clinical course and the magnetic resonance imaging (MRI) of the head and spine. The therapy comprises disease modifying drugs (DMD), therapy for acute relapses and escalation therapy according the German MS-Therapy-Consensus-Group (MSTKG). An early therapy initiation and a systematic therapy of acute relapses and symptoms determine the modern MS-management.

In patients with relapsing-remitting multiple sclerosis (MS), IVIG was shown to reduce the relapse rate and progression of disability. In patients with chronic progressive MS, a beneficial effect of IVIG was not documented in placebo controlled studies. This trial investigated the influence of IVIG in primary (PPMS) and secondary (SPMS) chronic progressive MS. Two-hundred and thirty-one patients stratified for PPMS ( n = 34) and SPMS ( n = 197) were randomly assigned to IVIG 0.4 g/kg per month or to placebo for 24 months. Primary endpoints were 1) the time to sustained progression of disease identified as worsening of the expanded disability status scale (EDSS) sustained for 3 months, and 2) the improvement of neurological functions defined by a patient's best EDSS score. Secondary endpoints were the proportion of patients with sustained progression, the relapse rate, the assessment of fine motor skills, visual evoked potentials, contrast sensitivity, depression and quality of life. Analysis of the intention-to-treat (ITT) population of combined PPMS and SPMS patients showed that the mean time to sustained progression was 74 weeks in the IVIG compared with 62 weeks in the placebo group ( P = 0.0406). When PPMS and SPMS patients were analysed separately, the time to sustained progression was also longer in the IVIG group, but the difference was not significant. There was no IVIG-mediated improvement in neurological functions. In the combined per protocol (PP) treated patients, IVIG treatment prolonged time to sustained progression by 13 weeks ( P = 0.0396). PPMS patients, but not SPMS patients showed a slight favourable IVIG effect on the best EDSS score. In the combined ITT population there were less patients with sustained progression in the IVIG than in the placebo group ( P = 0.028). The difference was significant in PPMS ( P = 0.016), but not in SPMS patients. In the combined PP population, there was a trend for a favorable IVIG effect on the rates of patients with sustained progression. In patients with PPMS, this IVIG effect reached significance ( P = 0.036). Other secondary endpoints did not show significant differences between treatment groups. Eighteen patients with PPMS and 102 patients with SPMS withdrew from the study for various reasons. Treatment was generally well tolerated. It was concluded that monthly IVIG infusion could delay progression of disease in patients with PPMS, and that there was a trend in favour of IVIG treatment in patients with SPMS. Multiple Sclerosis 2007; 13: 1107—1117. http://msj.sagepub.com

We studied two adult patients with myalgia and muscular fatigability during prolonged physical exercise. Serum creatine kinase was increased and muscle biopsy revealed a lipid storage myopathy affecting predominantly the type I fibres. Skeletal muscle carnitine content was reduced to 15% and 21% of the normal mean values, while serum carnitine levels were either normal or decreased. Four months of oral therapy with L-carnitine (3 g per day) resolved the clinical symptoms completely in both patients, and a subsequent muscle biopsy confirmed a marked reduction of lipid storage, along with increased muscle carnitine levels. The analysis of renal carnitine excretion and the exclusion of possible secondary carnitine deficiencies in both patients are compatible with mild defects of the carnitine transporter in one patient and of carnitine biosynthesis in the other. Since myalgia and muscular fatigue are frequent but unspecified complaints of otherwise clinically unremarkable adult patients, it is important to identify myopathies associated with primary carnitine deficiency because they may be amenable to treatment.

To assess whether TGF-beta isoforms are significantly increased after intravenous immunoglobulin (i.v.IG) infusion in the plasma of patients with multiple sclerosis (MS), 19 patients with clinically definite MS were enrolled in a double blind placebo controlled i.v.IG study. TGF-beta1, TGF-beta2, TGF-beta3 plasma concentrations were measured prior and directly after i.v.IG infusions by specific ELISA. Compared to the placebo group, we found a significant increase in the plasma levels of all three TGF-beta isoforms in patients treated with i.v.IG. The significantly increased TGF-beta plasma concentrations in treated patients suggest an additional, immediate mechanism of action that may accompany the molecular effects of i.v.IG therapy in MS. The variable amount of the potent anti-inflammatory TGF-beta isoforms within the i.v.IG preparations may exert a differentiated view regarding the manifold indications of i.v.IG therapy.

Nuclear power plants are operated in about 30 countries. The implementation of nuclear power plants in the future is being discussed in a similar number of other countries. Some of these plans are at an advanced stage; many others are at the stage of very preliminary considerations.

Logistics is concerned with effectively managing the flow of materials and supplies for production, commerce and other purposes (Christopher, 2003). Transport logistics deals with resource flows on a large scale level, as it involves transport by land, water, and air. A second domain of logistics is intralogistics, which is concerned with the internal handling of materials and supplies within specific production sites or intermediate storage facilities (Arnold, 2006). This paper focuses on intralogistics or, more specifically, on one of its central tasks, order picking.

OBJECTIVE—To assess the quality of life (QoL) of patients with multiple sclerosis in France, Germany, and the United Kingdom with a cross sectional study. METHODS—Patients were classified into three severity groups according to the expanded disability severity scale (EDSS); stage I, II, and III, corresponding to mild (EDSS 1.0-3.5), moderate (EDSS 4.0-6.0), or severe (EDSS 6.5-8.0) multiple sclerosis respectively. Ninety patients with multiple sclerosis and 30 control patients without multiple sclerosis were recruited in each country. Control patients were matched to the patients with multiple sclerosis according to age and sex. Quality of life was assessed using the functional status questionnaire (FSQ). RESULTS—The aspects of QoL that were mostly affected in the three countries under study were physical function and general wellbeing. Social role function decreased with increased severity of disease in France and in particular in Germany. Multiple sclerosis did not seem to have an impact on psychological function. The QoL of control patients was systematically higher than that of patients with multiple sclerosis. CONCLUSIONS—Use of such a generic scale showed that progression of multiple sclerosis is accompanied by a decrease in QoL and suggested that this could be a relevant measurement in assessing the effect of treatment and progression of disease. Variation between countries, however, may be important.

We present the design of a double-blind, randomised placebo-controlled phase III study to evaluate safety and efficacy of IVIG in the treatment of patients suffering from primary or secondary chronic progressive multiple sclerosis. The primary endpoint is disability. Two measures of disability were chosen in order to assess the primary end point: (a) sustained improvement (assessed at month 6, confirmed at month 9) and (b) progression to increasing disability of the disease (sustained for 3 months) at any time during the course of this 2 years study. The disability is measured by the Extended Disability Status Scale (EDSS). Secondary end points include the assessment of visual function, functions of the upper extremity, cognitive functions, depression and quality of life.

Background and purpose The trend towards a shorter stay in rehabilitation clinic has implications for future language therapy. Constraint-induced aphasia therapy (CIAT) is administered 3 h per day for a total of 30 h of treatment. It was evaluated for patients with chronic aphasia. In the present study we investigated the efficacy of a modified CIAT schedule and included patients with sub-acute stroke. We conducted a randomised, single-blind, parallel-group study. The results were compared to those of patients who received identically intensive treatment focusing on conventional aphasia therapy. Methods Fifty patients were treated with our modified version of CIAT and 50 received a standard aphasia therapy at the same intensity and duration. Inclusion criteria were clinical diagnosis of first-ever stroke, aphasia in the sub-acute stage and German speakers. Language function was evaluated using the Aachen Aphasia Test and the Communicative Activity Log directly before therapy onset, after the training period and at 8-week and 1-year follow-ups. Results Patients of both groups improved significantly in all sub-tests of the Aachen Aphasia Test Battery. The improvements remained stable over a 1-year follow-up period. Patients and relatives of both groups rated daily communication as significantly improved after therapy. Conclusions Both CIAT and conventional therapy performed with equal intensity are efficacious methods for patients with sub-acute aphasia. The modified CIAT schedule is practical in an everyday therapeutic setting. Our results indicate that a short-term intensive therapy schedule in the early aphasia stage leads to substantial improvements in language functions. Clinical Trial Registration Information Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01625676

Objective: To report the clinical and immunological response to immunosuppressive treatment with cyclophosphamide in two patients with paraneoplastic cerebellar degeneration. Design: Case reports. Clinical and immunological follow-up data were available for 4½ years in the first patient and for 2 years in the second patient. Setting: A 1500-bed university hospital and a 1200-bed university teaching hospital. Intervention: Cyclophosphamide intermittent treatment. Main Outcome Measure: Clinical disability. Results: One of the patients, who was treated from an early stage, recovered completely. The other patient showed a partial clinical response. While the two patients were receiving a maintenance regimen with cyclophosphamide, the conditions of both patients remained stable for at least 2 years. In both patients, intrathecal antibody synthesis declined considerably. Conclusion: Early induction of immunosuppressive therapy with cyclophosphamide should be tried in treating patients with paraneoplastic cerebellar degeneration.

Background: In multiple sclerosis inflammation is primarily injurious to the central nervous system, but its therapeutic suppression might inhibit repair-promoting factors. Objectives: We aimed at better describing the complexity of biological effects during an acute relapse and analysed the effects of intervention with high-dose i.v. glucocorticoids and immunomodulatory treatment with interferon-beta (IFNβ). Methods: We studied the intracellular expression levels of the pro-inflammatory mediators tumour necrosis factor alpha (TNFα) and inducible nitric oxide synthase (iNOS) together with the neurotrophins ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) in freshly isolated peripheral blood mononuclear cells of multiple sclerosis patients during an acute relapse, after intervention with i.v. methylprednisolone and at baseline, using a highly quantitative flow-cytometric approach. Results: We demonstrated the expression of CNTF in human leucocytes. We showed that CNTF levels differed in acutely relapsing multiple sclerosis patients compared with controls and increased after corticosteroid treatment. CNTF can counteract the toxicity of TNFα towards oligodendrocytes and we found TNFα increased during acute relapses. Following corticosteroids, neither TNFα nor iNOS expression was reduced. Levels of BDNF were not affected by glucocorticoids, but increased during IFNβ therapy. However, IFNβ also increased the expression of iNOS and major histocompatibility complex class I (MHC-I), underlining its immunomodulatory potential. Conclusions: Multiple sclerosis patients might benefit from reparative, and not solely from anti-inflammatory, effects of glucocorticoids. Interactive effects of glucocorticoid- and IFNβ-treatment need to be considered to improve neuroprotection and remyelination resulting from immunomodulatory treatment.

1477-0970 (Electronic) 1352-4585 (Linking) Journal Article; This study was performed to assess the temporal evolution of damage within lesions and the normal-appearing white matter, measured using frequent magnetization transfer (MT) MRI, in relapsing-remitting multiple sclerosis (RRMS). The relationship of MT ratio (MTR) changes with measures of lesion burden, and the sample sizes needed to demonstrate a treatment effect on MTR metrics in placebo-controlled MS trials were also investigated. Bimonthly brain conventional and MT MRI scans were acquired from 42 patients with RRMS enrolled in the placebo arm of a 14-month, double-blind trial. Longitudinal MRI changes were evaluated using a random effect linear model accounting for repeated measures, and adjusted for centre effects. The Expanded Disability Status Scale (EDSS) score remained stable over the study period. A weak, but not statistically significant, decrease over time was detected for normal-appearing brain tissue (NABT) average MTR (-0.02% per visit; p = 0.14), and MTR peak height (-0.15 per visit; p = 0.17), while average lesion MTR showed a significant decrease over the study period (-0.07% per visit; p = 0.03). At each visit, all MTR variables were significantly correlated with T2 lesion volume (LV) (average coefficients of correlation ranging from -0.54 to -0.28, and p-values from

Background Detecting malingering or exaggeration of impairments in brain function after traumatic brain injury is of increasing importance in neuropsychological assessment. Lawyers involved in brain injury litigation cases routinely coach their clients how to approach neuropsychological testing to their advantage. Thus, it is important to know how robust assessment methods are with respect to symptom malingering or exaggeration. Methods The influence of different coaching methods on the simulated malingering of memory impairments is investigated in neurologically healthy participants using the Short-Term-Memory Test from the Bremer Symptom-Validierung (STM-BSV). Cut-offs were derived from patients with mild to severe traumatic brain injury. For comparison purposes, the German adaptation of the Rey Auditory Verbal Learning Test (AVLT), and the Rey 15 Items Test (FIT) were additionally administered. Four groups of neurologically healthy subjects were instructed to (1) perform as best as they can, (2) simulate brain injury, (3) simulate brain injury and received additional information about the sequelae of head trauma, (4) simulate brain injury and received additional information on how to avoid detection. Furthermore, a group of patients with mild to severe closed head injury performed the tests with best effort. Results The naïve simulator and the symptom coached groups were the easiest to detect, whereas the symptom plus test coached group was the hardest to detect. The AVLT and the FIT were not suited to detect simulators (sensitivities from 0% to 50.8% at 75% specificity) whereas the STM-BSV detected simulators with 67% – 88% sensitivity at a specificity of 73%. However, the STM-BSV was not robust to coaching. Conclusion The present investigation shows that symptom validity testing as implemented in the BSV-STM is one clinically useful element in the detection of memory malingering. However, clinicians have to be aware that coaching influences performance in the test.

Background: Chronic immune-mediated demyelinating polyneuropathy (CIP) represents a heterogeneous pool of motor, sensory, sensorimotor, symmetric, or asymmetric syndromes. Objective: To evaluate published diagnostic classifications and characterize predictors of treatment response. Methods: One hundred two of 158 patients with a working diagnosis of CIP were included and clinically characterized because they had electrophysiologic and/or histologic evidence of demyelination. The biostatistical profile of patients with symmetric clinical manifestation was analyzed using three proposed classifications (American Academy of Neurology [AAN] criteria, modified AAN criteria, European Federation of Neurological Societies/Peripheral Nerve Society [EFNS/PNS] criteria). Treatment responses to IV immunoglobulins (IVIg) and their positive predictors were investigated. Results: Sensitivities (0.52 [AAN] vs 0.83 [modified AAN] vs 0.95 [EFNS/PNS]) and negative predictive values (0.68 vs 0.85 vs 0.92) differed markedly, whereas specificities (0.94 vs 0.90 vs 0.96) and positive predictive values (0.89 vs 0.89 vs 0.97) were similar. In CIP patients treated with IVIg, a positive response was found in 62 of 76 (82%). Patients with a monophasic or relapsing–remitting course or a more than twofold CSF protein increase had the highest probability to respond to IVIg, most evident when using the modified AAN criteria. Conclusions: The European Federation of Neurological Societies/Peripheral Nerve Society criteria for chronic inflammatory demyelinating polyneuropathy improve treatment of patients with chronic immune-mediated demyelinating polyneuropathy, particularly with respect to diagnostic issues. To predict IV immunoglobulin treatment response, the modified American Academy of Neurology criteria are the most valuable classification provided an increased CSF protein level.

Defining tools in magnetic resonance imaging (MRI) representing specific pathological processes is needed to understand the complex relationship between inflammation, myelin breakdown, axonal injury and clinical symptoms in multiple sclerosis (MS) and its variants. Here, we describe a case of histologically-defined MS, in which the radiological appearance of the lesion and clinical course support the diagnosis of Balo's concentric sclerosis. Serial magnetization transfer, diffusion tensor imaging and 1H-magnetic resonance spectroscopy, from 14 days to 13 months after biopsy, allow the contextual interpretation of specific pathological changes. In our case, acute inflammation was sensitively traced by fractional anisotropy and increased lactate in spectroscopy. In contrast, magnetization transfer ratio and the apparent diffusion coefficient monitor the sequential loss of tissue in selected rings of the lesion. The delay from the peak of symptoms in a dramatic clinical course to the maximum tissue destruction indicated through MRI suggests that compromise of axonal function may be decisive for the acute clinical situation. This is the first report comparing 1Hmagnetic resonance spectroscopy, magnetization transfer and diffusion tensor imaging with histopathology in a patient with Balo's concentric sclerosis. Multiple Sclerosis 2007; 13: 471-482. http://msj.sagepub.com

Background: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a heterogenous disease of probably autoimmune origin. Recently published criteria give consideration to its clinical heterogeneity as well as to the impact of positive treatment response in making the diagnosis ex iuvantibus. Beyond intravenous immunoglobulins (IVIg), steroids, azathioprine, mycophenolate, ciclosporine, cyclophosphamide or plasma exchange are accepted as standard or escalating treatment options. Objective: To define the positive predictive value for treatment response of elevated cerebrospinal fluid (CSF) protein in CIDP patients. Patients and methods: CSF protein pre-treatment levels at time of diagnosis of 72 patients with positive EFNS criteria for CIDP were analysed retrospectively. CSF protein up to 420mg/l was assessed to be normal. For statistical analysis total positive rate (TPR); total negative rate (TNR), positive and negative preditive values (PPV, NPV), and finally likelihood ratios (LHR) were calculated to evaluate positive tretament prediction. Results: The LHR of patients with a more than than two-fold increase in CSF protein (i.e. >840mg/l) and IVIg application was 2.5 and their PPV 91% (TPR 0.55, TNR 0.78, NPV 0.29). Other immune therapies did not show higher LHR in these patients. Conclusion: The odds for a positive treatment response to IVIg is 2.5-fold higher in CIDP patients with CSF protein elevation >840mg/l than in patients with lower CSF values. Prospective data should be collected to prove the clinical validity and usefulness of CSF protein elevation as a predictive marker in CIDP.

In patients with isolated syndromes that are clinically suggestive of multiple sclerosis, such as optic neuritis or brain-stem or spinal cord syndromes, the presence of lesions as determined by T2-weighted magnetic resonance imaging (MRI) of the brain increases the likelihood that multiple sclerosis will develop. We sought to determine the relation between early lesion volume, changes in volume, and long-term disability.Seventy-one patients in a serial MRI study of patients with isolated syndromes were reassessed after a mean of 14.1 years. Disability was measured with the use of Kurtzke's Expanded Disability Status Scale (EDSS; possible range, 0 to 10, with a higher score indicating a greater degree of disability).Clinically definite multiple sclerosis developed in 44 of the 50 patients (88 percent) with abnormal results on MRI at presentation and in 4 of 21 patients (19 percent) with normal results on MRI. The median EDSS score at follow-up for those with multiple sclerosis was 3.25 (range, 0 to 10); 31 percent had an EDSS score of 6 or more (including three patients whose deaths were due to multiple sclerosis). The EDSS score at 14 years correlated moderately with lesion volume on MRI at 5 years (r=0.60) and with the increase in lesion volume over the first 5 years (r=0.61).In patients who first present with isolated syndromes suggestive of multiple sclerosis, the increases in the volume of the lesions seen on magnetic resonance imaging of the brain in the first five years correlate with the degree of long-term disability from multiple sclerosis. This relation is only moderate, so the volume of the lesions alone may not be an adequate basis for decisions about the use of disease-modifying treatment.

Central nervous system (CNS) involvement in systemic lupus erythematosus (SLE) remains difficult to diagnose, particularly since structural abnormalities may not be revealed by magnetic resonance imaging (MRI). Glucose utilisation was measured by positron emission tomography (PET) in 35 SLE patients to detect signs of CNS involvement. The patients were examined by a standardised neurological examination, a battery of tests to evaluate neuropsychological performance and MRI. Antineuronal antibodies were determined to investigate their putative role in CNS involvement in SLE. Twenty patients had distinct neurological (17) and/or psychiatric (3) symptoms. Ten patients had pronounced cognitive impairment. Neurological and cognitive deficits were thus found to be unrelated disorders in SLE. Global glucose utilisation of SLE patients did not differ significantly from that of normal controls, nor were differences found between SLE patients with or without neurological or cognitive abnormalities. On MRI of the brain, the number and size of white matter lesions correlated with the presence of neurological deficits but were unrelated to the severity of cognitive impairment. Within the normal range, lower global glucose utilisation tended towards lower values with increasing number and size of white matter lesions. Patients with lesions larger than 8 mm also showed distinctly increased IgG anticardiolipin antibody titres, whereas measuring antineuronal antibodies did not reveal any relation to the variables investigated. We conclude that the demonstration of CNS lesions by MRI can contribute confirmatory evidence for CNS involvement in SLE, but PET or the presence of antineuronal antibodies adds little if any information beyond that obtained by clinical examination, neuropsychological testing, and MRI.