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Mycobacteroides abscessus is one of the most resistant bacteria so far known and causes severe and hard to treat lung infections in predisposed patients such as those with Cystic Fibrosis (CF). Further, it causes nosocomial infections by forming biofilms on medical devices or water reservoirs. An eye-catching feature of M. abscessus is the growth in two colony morphotypes. Depending on the presence or absence of glycopeptidolipids on the cell surface, it forms smooth or rough colonies. In this study, a porous glass bead biofilm model was used to compare biofilm formation, biofilm organization and biofilm matrix composition in addition to the antimicrobial susceptibility of M. abscessus biofilms versus suspensions of isogenic (smooth and rough) patient isolates. Both morphotypes reached the same cell densities in biofilms. The biofilm architecture, however, was dramatically different with evenly distributed oligo-layered biofilms in smooth isolates, compared to tightly packed, voluminous biofilm clusters in rough morphotypes. Biofilms of both morphotypes contained more total biomass of the matrix components protein, lipid plus DNA than was seen in corresponding suspensions. The biofilm mode of growth of M. abscessus substantially increased resistance to the antibiotics amikacin and tigecycline. Tolerance to the disinfectant peracetic acid of both morphotypes was increased when grown as biofilm, while tolerance to glutaraldehyde was significantly increased in biofilm of smooth isolates only. Overall, smooth colony morphotypes had more pronounced antimicrobial resistance benefit when growing as biofilm than M. abscessus showing rough colony morphotypes.

We provide a proof and a counterexample to two conjectures made by N. Kuznetsov.

Abstract Background Currently, there are several studies showing that wearable inertial sensors are highly sensitive in the detection of gait disturbances in people with multiple sclerosis (PwMS), showing excellent reliability within one or 7–14 days. However, it is not known how stable these gait parameters remain over a longer period of time. This is surprising, because many treatments last longer than two weeks. Thus, the purpose of the current study was to examine gait parameters obtained by means of wearable inertial sensors during a 6-min walk and to reassess these parameters after a period of one year. Methods Fifty PwMS (without a relapse or a recent change in the Expanded Disability Status Scale (EDSS) or treatment) and 20 healthy participants were examined at two assessment points (interval between assessments: 14.4 ± 6.6 months). At each assessment point, all participants had to complete a 6-min walking test, an observer-rater test (Berg Balance Scale, BBS) and a Timed-up and Go Test (TUG). To measure mean gait parameters (i.e. walking speed, stride length, stride time, the duration of the stance and swing phase and minimum toe-to-floor distance), as well as the intraindividual standard deviation of each mean gait parameter, wearable inertial sensors were utilized. Results We found that even after one year all mean gait parameters showed excellent Intraclass Correlation Coefficients (ICC between 0.75 and 0.95) in PwMS. Looking at MS subgroups, the ICCs were slightly higher in MS subgroup 2 (EDSS 2.0–5.0) than those in MS subgroup 1 (EDSS 0.0–1.5) and healthy controls. Compared to the mean gait parameters, parameters of gait variability showed only good-to-fair ICC values in PwMS. Concerning BBS and TUG, the ICC values after one year were close to the ICC values of the measured mean gait parameters. Conclusions Due to the excellent stability of mean gait parameters after one year, these sensor-based gait parameters can be identified as clinically relevant markers to evaluate treatment effects over a longer (several months) period of time in MS.

Orbitrap mass spectrometry in full scan mode enables the simultaneous detection of hundreds of metabolites and their isotope-labeled forms. Yet, sensitivity remains limiting for many metabolites, including low-concentration species, poor ionizers, and low-fractional-abundance isotope-labeled forms in isotope-tracing studies. Here, we explore selected ion monitoring (SIM) as a means of sensitivity enhancement. The analytes of interest are enriched in the orbitrap analyzer by using the quadrupole as a mass filter to select particular ions. In tissue extracts, SIM significantly enhances the detection of ions of low intensity, as indicated by improved signal-to-noise (S/N) ratios and measurement precision. In addition, SIM improves the accuracy of isotope-ratio measurements. SIM, however, must be deployed with care, as excessive accumulation in the orbitrap of similar m/z ions can lead, via space-charge effects, to decreased performance (signal loss, mass shift, and ion coalescence). Ion accumulation can be controlled by adjusting settings including injection time and target ion quantity. Overall, we suggest using a full scan to ensure broad metabolic coverage, in tandem with SIM, for the accurate quantitation of targeted low-intensity ions, and provide methods deploying this approach to enhance metabolome coverage.

BackgroundGait variability in people with multiple sclerosis (PwMS) reflects disease progression or may be used to evaluate treatment response. To date, marker-based camera systems are considered as gold standard to analyze gait impairment in PwMS. These systems might provide reliable data but are limited to a restricted laboratory setting and require knowledge, time, and cost to correctly interpret gait parameters. Inertial mobile sensors might be a user-friendly, environment- and examiner-independent alternative. The purpose of this study was to evaluate the validity of an inertial sensor-based gait analysis system in PwMS compared to a marker-based camera system.MethodsA sample N = 39 PwMS and N = 19 healthy participants were requested to repeatedly walk a defined distance at three different self-selected walking speeds (normal, fast, slow). To measure spatio-temporal gait parameters (i.e., walking speed, stride time, stride length, the duration of the stance and swing phase as well as max toe clearance), an inertial sensor system as well as a marker-based camera system were used simultaneously.ResultsAll gait parameters highly correlated between both systems (r > 0.84) with low errors. No bias was detected for stride time. Stance time was marginally overestimated (bias = −0.02 ± 0.03 s) and gait speed (bias = 0.03 ± 0.05 m/s), swing time (bias = 0.02 ± 0.02 s), stride length (0.04 ± 0.06 m), and max toe clearance (bias = 1.88 ± 2.35 cm) were slightly underestimated by the inertial sensors.DiscussionThe inertial sensor-based system captured appropriately all examined gait parameters in comparison to a gold standard marker-based camera system. Stride time presented an excellent agreement. Furthermore, stride length and velocity presented also low errors. Whereas for stance and swing time, marginally worse results were observed.

Abstract Background Diagnostics of Alzheimer’s Disease (AD) require a multimodal approach. Neuropsychologists examine the degree and etiology of dementia syndromes and results are combined with those of cerebrospinal fluid markers and imaging data. In the diagnostic process, neuropsychologists often rely on anamnestic and clinical information, as well as cognitive tests, prior to the availability of exhaustive etiological information. The congruency of this phenomenological approach with results from FDG-PET/CT examinations remains to be explored. The latter yield highly accurate diagnostic information. Method A mixed sample of N = 127 hospitalized neurological patients suspected of displaying a dementia syndrome underwent extensive neuropsychological and FDG-PET/CT examinations. Neuropsychological examinations included an anamnestic and clinical interview, and the CERAD cognitive test battery. Two decisional approaches were considered: First, routine diagnostic results were obtained, i.e. the final clinical decision of the examining neuropsychologist (ADClinical vs. non-ADClinical). Secondly, a logistic regression model was implemented, relying on CERAD profiles alone. CERAD subscales that best predicted AD based on FDG-PET/CT were identified and a nominal categorization obtained (ADTest vs. non-ADTest). Congruency of results from both approaches with those of the FDG-PET/CT (ADPET vs. non-ADPET) were estimated with Cohen’s Kappa (κ) and Yule’s Y coefficient of colligation. Descriptive estimates of accuracy, sensitivity and specificity of CERAD relative to FDG-PET/CT diagnostics were derived. Results ADPET patients constituted N = 33/127 (26%) of the sample. The clinical decision approach (ADClinical vs. non-ADClinical) showed substantial agreement with the FDG-PET/CT classification (κ = .69, Y = .72) involving good accuracy (84.2%), moderate sensitivity (75.8%) and excellent specificity (92.6%). In contrast, the decisional approach that relied on CERAD data alone (ADTest vs. non-ADTest) involved only moderate agreement with the FDG-PET/CT (κ = .54, Y = .62) with lower accuracy (74.8%), attributable to decreased sensitivity (56.3%) and comparable specificity (93.3%). Conclusions It is feasible to identify AD through a comprehensive neuropsychological examination in a mixed sample of neurological patients. However, within the boundaries of methods applied here, decisions based on cognitive test results alone appear limited. One may conclude that the clinical impression based on anamnestic and clinical information obtained by the neuropsychological examiner plays a crucial role in the identification of AD patients in routine clinical practice.

Abstract Objectives Persons with MS (PwMS) are frequently affected by fatigue and depression. Mindfulness-based interventions may reduce these symptoms in PwMS and consequently their application has been extended to various settings. Only few efforts have been made to explore effects of short-term mindfulness training during brief periods of hospitalization. In the current study, the feasibility and potential effects of short-term mindfulness training on depression, fatigue, rumination and cognition were explored in PwMS in an acute-care hospital setting. Based on previous work, it was further examined whether the relation between trait mindfulness and fatigue prior to and following the intervention was mediated by depression and whether a mediation effect was also observable throughout the intervention. Methods A short-term mindfulness training protocol was developed, tailored to the requirements of the acute-care setting. Subsequently, 30 PwMS were recruited sequentially and received mindfulness training during the routine clinical process (median duration in hospital: eight days, number of sessions: four). Participants completed relevant self-report measures (depression, fatigue, rumination) and a neuropsychological assessment before and after training. Results Participants reported significantly increased trait mindfulness and decreased depression and fatigue following the intervention. Respective change scores were highly correlated so that increased trait mindfulness was associated with decreased symptoms. In the rumination domain, patients reported a tendency for an increased adaptive ability to engage in distractive behavior during arising negative mood. Other measures of trait rumination and cognition remained relatively stable. Results of the mediation analyses indicated that depression mediated the negative relationship between trait mindfulness and fatigue symptoms at pre and post assessments. With regards to the change scores, an association between mindfulness and cognitive fatigue ceased to be significant when depression was controlled, albeit in this case, the mediation effect did not reach significance. Conclusion Results of the current study indicate that short-term mindfulness training during brief periods of hospitalization may be beneficial for PwMS. They further complement previous work by identifying depression as a potential mediator of the antagonistic relationship between mindfulness and fatigue. Based on the current exploratory study, future trials are warranted to address this mechanism of mindfulness training in more detail.

Abstract Background The aim of the current study was to examine multiple gait parameters obtained by wearable inertial sensors and their sensitivity to clinical status in early multiple sclerosis (MS). Further, a potential correlation between gait parameters and subjective fatigue was explored. Methods Automated gait analyses were carried out on 88 MS patients and 31 healthy participants. To measure gait parameters (i.e. walking speed, stride length, stride duration, duration of stance and swing phase, minimal toe-to-floor distance), wearable inertial sensors were utilized throughout a 6-min 25-ft walk. Additionally, self-reported subjective fatigue was assessed. Results Mean gait parameters consistently revealed significant differences between healthy participants and MS patients from as early as an Expanded Disability Status Scale (EDSS) value of 1.5 onwards. Further, MS patients showed a significant linear trend in all parameters, reflecting continuously deteriorating gait performance throughout the test. This linear deterioration trend showed significant correlations with fatigue. Conclusions Wearable inertial sensors are highly sensitive in the detection of gait disturbances, even in early MS, where global scales such as the EDSS do not provide any clinical information about deviations in gait behavior. Moreover, these measures provide a linear trend parameter of gait deterioration that may serve as a surrogate marker of fatigue. In sum, these results suggest that classic timed walking tests in routine clinical practice should be replaced by readily and automatically applicable gait assessments, as provided by inertial sensors.

Barbara Plagg,1,2 Giuliano Piccoliori,1 Jörg Oschmann,3 Adolf Engl,1 Klaus Eisendle1,4 1Institute of General Practice and Public Health - College of Health Care Professions Claudiana, Bolzano, Italy; 2Free University of Bozen/Bolzano, Bolzano, Italy; 3Institute of Cultural and Social Anthropology, Ludwig Maximilians University, Munich, Germany; 4Central Hospital Bolzano/Bozen, Bolzano, ItalyCorrespondence: Barbara Plagg Email barbara.plagg@unibz.itAbstract: The pandemic due to SARS-CoV-2 tested the resilience of health systems worldwide. The outcome of the pandemic is impacted by health management choices made over the course of the disaster, which in turn are strongly dependent on the underlying healthcare system – as mirrored by the fact that regional pandemic experiences differ considerably: In Italy (a country most impacted by the COVID-19 outbreak), infection and mortality rates vary vastly between regions, with Lombardy – a comparatively well-equipped region with regard to hospitals and centers of scientific excellence – being amongst the worst-affected areas. Within this article, we focus on the challenges within primary health care and hospital organization, cooperation between primary and specialist care, and access to health care services: In Lombardy, neglected primary health care with a comparatively low availability of general practitioners (GPs) per inhabitant, the initial prioritization of hospitals during the pandemic while neglecting primary health care in terms of personal protective equipment (PPE), the lack of testing resources, and a failure to achieve coordinated support contributed to a quick overburdening of hospitals, where the dissolution of traditional departments into “macro-areas” may favor nosocomial infections during an ongoing pandemic. Neither specialized medicine nor privatization, but rather flexible public healthcare services working in consistent cooperation with GPs, show better efficiency in containing viral spread and managing patients. Strengthening the primary health care sector with regard to human and technical resources and supporting the coordination between the different levels of health care providers help to avoid overcrowded hospitals, while protecting patients and health care workers during large-scale health emergencies. Overall, further in-depth analysis of structural determinants is needed in order to develop more-resilient and integrative health care systems.Keywords: COVID-19, disaster management, primary health care, intensity of care hospitals, continuity of care, integration of care

Borries Kukowski,1 Karin Rehberg-Weber,2 Kirsi Taipale,2 Andreas Kowalik,3 Patrick Oschmann4 1Neurologische Gemeinschaftspraxis, Göttingen, Germany; 2Biogen GmbH, Munich, Germany; 3Praxis Dr. Kowalik, Stuttgart, Germany; 4Klinik für Neurologie, Klinikum Bayreuth GmbH, Bayreuth, GermanyCorrespondence: Borries KukowskiNeurologische Gemeinschaftspraxis, Groner-Tor-Straße 3, Göttingen, 37073, GermanyTel +49 551 46069Fax +49 551 55172Email praxis@drkukowski.dePurpose: The purpose of this study was to assess the prevalence of injection site reactions (ISR) and flu-like symptoms (FLS) during treatment with subcutaneous (SC) interferon (IFN) beta therapies and to document measures to mitigate and prevent ISR and FLS.Patients and Methods: The cross-sectional post-authorization safety study PERFECT was conducted from 11/2017 to 7/2019 in neurology practices in Germany. Adult patients with relapsing-remitting multiple sclerosis (MS) receiving SC IFN beta for ≥ 3 months were eligible. The primary endpoints were patient-reported prevalence of ISR and FLS. Additional endpoints reported by patients, MS nurses, and neurologists included type, frequency, duration, time of occurrence, and management of ISR and FLS.Results: In total, 603 patients (median age 45 years [range 36– 53], 74% female) were included in the analysis. Time since MS diagnosis was > 5 years in most patients. The majority had received none (64%) or 1 (22%) prior therapy. Current MS therapy in 36%, 32%, and 30% of patients was IFN beta-1b, IFN beta-1a, and peginterferon beta-1a, respectively. ISR and FLS under current therapy were reported by 84% and 68% of patients, respectively. ISR developed within 5 days after injection (84%) and lasted for 2– 14 days (53%) in most patients. The most frequent patient-reported symptom was erythema (39%). ISR resolved or abated with systemic treatments or topical ointments. Most frequent preventive measures included alternating injection sites (58%). Occurrence of ISR rarely resulted in treatment interruption (5%). FLS occurred predominantly up to 6 h after injection (40%) and lasted < 12 h (26%). The most frequent patient-reported symptoms were fatigue (15%) and aching limbs (15%). Assessments by physicians and MS nurses differed from patient-reported results.Conclusion: Although ISR were experienced by the majority of patients, they rarely resulted in treatment interruption. In this real-world setting, ISR and FLS management was in line with published expert recommendations.Keywords: peginterferon beta-1a, post-authorization safety study, real-world, erythema, disease-modifying therapy

Abstract Objectives Persons with MS (PwMS) often display symptoms of depression and fatigue. Mindfulness-based interventions are known to counteract these symptoms. However, to-date the exact relations between trait mindfulness, depression and fatigue remain to be examined. Fatigue is generally regarded as a symptom immanent to the disease and as a direct neurobiological consequence of increased cytokine levels and cortical atrophy. In depression on the other hand, psychosocial factors in the context of adaptation difficulties are probably of higher relevance. Hence, one may argue that mindfulness, as a trait that promotes successful adaption, may show a strong negative association with depression and a relatively minor negative association with fatigue in PwMS. Methods In the current study, the association between self-reported trait mindfulness, fatigue and depression was examined in a sample of 69 PwMS. Results Trait mindfulness showed highly significant negative correlations with both, depression and fatigue. Mediation analyses however, revealed that depression mediated the relation between mindfulness and fatigue. Conclusion It may be concluded that in PwMS, trait mindfulness shows a genuine negative association with depression, but that it is only secondarily associated with fatigue. Implications for mindfulness-based interventions in MS are discussed. Based on the results of the current study, it may be feasible to promote the acceptance of default fatigue symptoms, instead of an actual reduction of fatigue symptoms.

Abstract Background The number of total knee replacements (TKRs) and total hip replacements (THRs) has been increasing noticeably in high-income countries, such as Germany. In particular, the number of revisions is expected to rise because of higher life expectancy and procedures performed on younger patients, impacting the budgets of health-care systems. Quality transparency is the basis of holistic patient pathway optimization. Nevertheless, a nation-wide cross-sectoral assessment of quality from a patient perspective does not yet exist. Several studies have shown that the use of patient-reported outcome measures (PROMs) is effective for measuring quality and monitoring post-treatment recovery. For the first time in Germany, we test whether early detection of critical recovery paths using PROMs after TKR/THR improves the quality of care in a cost-effective way and can be recommended for implementation into standard care. Methods/design The study is a two-arm multi-center patient-level randomized controlled trial. Patients from nine hospitals are included in the study. Patient-centered questionnaires are employed to regularly measure digitized PROMs of TKR/THR patients from the time of hospital admission until 12 months post-discharge. An expert consortium has defined PROM alert thresholds at 1, 3, and 6 months to signal critical recovery paths after TKR/THR. An algorithm alerts study assistants if patients are not recovering in line with expected recovery paths. The study assistants contact patients and their physicians to investigate and, if needed, adjust the post-treatment protocol. When sickness funds’ claims data are added, the cost-effectiveness of the intervention can be analyzed. Discussion The study is expected to deliver an important contribution to test PROMs as an intervention tool and examine the determinants of high-quality endoprosthetic care. Depending on a positive and cost-effective impact, the goal is to transfer the study design into standard care. During the trial design phase, several insights have been discovered, and there were opportunities for efficient digital monitoring limited by existing legacy care models. Digitalization in hospital processes and the implementation of digital tools still represent challenges for hospital personnel and patients. Furthermore, data privacy regulations and the separation between the in- and outpatient sector are roadblocks to effectively monitor and assess quality along the full patient pathway. Trial registration German Clinical Trials Register: DRKS00019916 . Registered November 26, 2019 – retrospectively registered.

Research-learning projects (RLP) enable teacher training students to acquire competencies for evidence-based practice (EBP) in the context of their university studies. The aim of this longitudinal study is to develop, implement, and evaluate a RLP format to promote competencies for EBP in teacher training students. These competencies can be broken down into the categories of using research, which involves reflection on and use of evidence to solve problems in teaching practice, and establishing research, which involves investigating a research question independently by applying research methods. In a longitudinal study we evaluate the increase in competencies based on a self-assessment of competencies (indirect measurement) focusing on establishing research, and a competence test (direct measurement) focusing on using research. We also add a retrospective pre-assessment version (quasi-indirect measurement) to consider response shift and over- or underestimation in self-assessments. Our findings show that teacher training students can be prepared for EBP through RLP. Further development potential for the RLP format is being discussed.

Background: With a large array of disease modifying therapies (DMTs) for relapsing-remitting MS (RRMS), identifying the optimal treatment option for the individual patient is challenging and switching of immunotherapies is often required. The objective of this study was to systematically investigate reasons for DMT switching in patients on immunotherapies for mild/moderate MS, and provide real-life insights into currently applied therapeutic strategies. Methods: This noninterventional, cross-sectional study (ML29913) at 50 sites in Germany included RRMS patients on therapies for mild/moderate MS who switched immunotherapy in the years 2014–2017. The key outcome variable was the reason to switch, as documented in the medical charts, based on failure of current therapy, cognitive decline, adverse events (AEs), patient wish, or a woman’s wish to become pregnant. Expectations of the new DMT and patients’ assessment of the decision maker were also recorded. Results: The core analysis population included 595 patients, with a mean age of 41.6 years, of which 69.7% were female. More than 60% of patients had at least one relapse within 12 months prior to the switch. The main reasons to switch DMT were failure of current therapy (53.9%), patient wish (22.4%), and AEs (19.0%). Most patients (54.3%) were switched within DMTs for mild/moderate MS; only 43.5% received a subsequent DMT for active/highly active MS. While clinical and outcome-oriented aspects were the most frequently mentioned expectations of the new DMT for physicians, aspects relating to quality of life played a major role for patients. Conclusions: Our data indicate suboptimal usage of DMTs, including monoclonal antibodies, for active/highly active MS in German patients. This illustrates the medical need for DMTs combining high efficacy, low safety risk, and low therapy burden.

The evaluation of local divergence exponent (LDE) has been proposed as a common gait stability measure in people with multiple sclerosis (PwMS). However, differences in methods of determining LDE may lead to different results. Therefore, the purpose of the current study was to determine the effect of different sensor locations and LDE measures on the sensitivity to discriminate PwMS. To accomplish this, 86 PwMS and 30 healthy participants were instructed to complete a six-minute walk wearing inertial sensors attached to the foot, trunk and lumbar spine. Due to possible fatigue effects, the LDE short (~50% of stride) and very short (~5% of stride) were calculated for the remaining first, middle and last 30 strides. The effect of group (PwMS vs. healthy participants) and time (begin, mid, end) and the effect of Expanded Disability Status Scale (EDSS) and time were assessed with linear random intercepts models. We found that perturbations seem to be better compensated in healthy participants on a longer time scale based on trunk movements and on a shorter time scale (almost instantaneously) according to the foot kinematics. Therefore, we suggest to consider both sensor location and time scale of LDE when calculating local gait stability in PwMS.

This paper describes the controlled radical polymerization of an ionic-liquid monomer by RAFT polymerization. This allows the control over the molecular weight of ionic liquid blocks in the range of 8000 and 22000 and of the block-copolymer synthesis. In this work we focus on block copolymers with an anchor block. They can be used to control the formation of TiO2 nanoparticles, which are functionalized thereafter with a block of ionic-liquid polymer. Pyrolysis of these polymer functionalized inorganic nanoparticles leads to TiO2 nanoparticles coated with a thin carbonaceous shell. Such materials may, e.g., be interesting as battery materials.

Background: Cognitive deficits including impaired information processing speed as assessed by the Symbol Digit Modalities Test (SDMT) are common in multiple sclerosis (MS). Oscillatory markers of processing speed may be extracted from magnetoencephalographic (MEG) and electroencephalographic (EEG) resting-state recordings. In this context, an increased proportion of frontal slow-wave (theta, 4–8 Hz) to fast-wave (beta, 13–30 Hz) EEG activity was indicative of impaired SDMT performance. Such an increased theta/beta ratio may reflect oscillatory slowing associated with deficits in attention control. Therapeutic approaches that consider atypical oscillatory activity in MS remain sparse. Objectives: In a cross-sectional design, we examined the relation between SDMT performance, the EEG theta/beta ratio and its components. We also explored longitudinally, whether EEG neurofeedback could be used to induce a putatively adaptive alteration in these EEG parameters, toward a pattern indicative of improved processing speed. Methods: N = 58 MS patients (RRMS/SPMS/PPMS N: 18/35/3, 2 cases excluded) participated in a neuropsychological examination and a resting-state EEG recording. Subsequently, N = 10 patients received neurofeedback training for two weeks in a hospitalized setting. The purpose was to reduce the frontal theta/beta ratio through operant conditioning. Results: In the cross-sectional examination, patients with slow SDMT speed displayed an increased theta/beta ratio, relative to those with normal speed. This involved increased frontal theta power, whereas beta power was equal across groups. The theta/beta ratio remained stable during neurofeedback across sessions of the two-week training period. In an exploratory secondary analysis, within sessions a reduction in the theta/beta ratio during active training blocks relative pre/post session resting-states was observed, driven by reduced theta power. Conclusions: These findings provide support for utilizing frontal EEG theta activity as an inverse marker of processing speed in MS. Across sessions, there was no support for successful operant conditioning of the theta/beta ratio during the two-week training period. The observed state-specific shift within sessions, involving a transient reduction in theta activity, nevertheless may provide a rationale for a further investigation of neurofeedback as a treatment approach in MS. Keywords: Multiple sclerosis (MS), Symbol digit modalities test (SDMT), Neurofeedback, Electroencephalogram (EEG), Attention

Herein, we present a short and highly modular synthetic route that involves 8-aminoquinoline directed C−H arylation and transamidation chemistry, and which enables access to a wide range of elaborate benzofuran-2-carboxamides. For the directed C−H arylation reactions, Pd catalysis was used to install a wide range of aryl and heteroaryl substituents at the C3 position of the benzofuran scaffold in high efficiency. Directing group cleavage and further diversification of the C3-arylated benzofuran products were then achieved in a single synthetic operation through the utilization of a one-pot, two-step transamidation procedure, which proceeded via the intermediate N-acyl-Boc-carbamates. Given the high efficiency and modularity of this synthetic strategy, it constitutes a very attractive method for generating structurally diverse collections of benzofuran derivatives for small molecule screening campaigns.

Astrocytes integrate and process synaptic information and exhibit calcium (Ca2+) signals in response to incoming information from neighboring synapses. The generation of Ca2+ signals is mostly attributed to Ca2+ release from internal Ca2+ stores evoked by an elevated metabotropic glutamate receptor (mGluR) activity. Different experimental results associated the generation of Ca2+ signals to the activity of the glutamate transporter (GluT). The GluT itself does not influence the intracellular Ca2+ concentration, but it indirectly activates Ca2+ entry over the membrane. A closer look into Ca2+ signaling in different astrocytic compartments revealed a spatial separation of those two pathways. Ca2+ signals in the soma are mainly generated by Ca2+ release from internal Ca2+ stores (mGluR-dependent pathway). In astrocytic compartments close to the synapse most Ca2+ signals are evoked by Ca2+ entry over the plasma membrane (GluT-dependent pathway). This assumption is supported by the finding, that the volume ratio between the internal Ca2+ store and the intracellular space decreases from the soma towards the synapse. We extended a model for mGluR-dependent Ca2+ signals in astrocytes with the GluT-dependent pathway. Additionally, we included the volume ratio between the internal Ca2+ store and the intracellular compartment into the model in order to analyze Ca2+ signals either in the soma or close to the synapse. Our model results confirm the spatial separation of the mGluR- and GluT-dependent pathways along the astrocytic process. The model allows to study the binary Ca2+ response during a block of either of both pathways. Moreover, the model contributes to a better understanding of the impact of channel densities on the interaction of both pathways and on the Ca2+ signal.

Tubular carbonate concretions of up to 1 m in length and perpendicular to bedding, occur abundantly in the Upper Pliensbachian (upper Amaltheus margaritatus Zone, Gibbosus Subzone) in outcrops (Fontaneilles section) in the vicinity of Rivière-sûr-Tarn, southern France. Stable isotope analyses of these concretions show negative δ13C values that decrease from the rim to the center from −18.8‰ to −25.7‰ (V-PDB), but normal marine δ18O values (−1.8‰). Carbon isotope analyses of Late Pliensbachian bulk carbonate (matrix) samples from the Fontaneilles section show clearly decreasing C-isotope values across the A. margaritatus Zone, from +1‰ to −3‰ (V-PDB). Isotope analyses of coeval belemnite rostra do not document such a negative C-isotope trend with values remaining stable around +2‰ (V-PDB). Computer tomographic (CT) scanning of the tubular concretions show multiple canals that are lined or filled entirely with pyrite. Previously, the formation of these concretions with one, two, or more central tubes, has been ascribed to the activity of an enigmatic organism, possibly with annelid or arthropod affinities, known asTisoa siphonalis. Our results suggest tisoan structures are abiogenic. Based on our geochemical analyses and sedimentological observations we suggest that these concretions formed as a combination of the anaerobic oxidation of methane (AOM) and sulfate reduction within the sediment. Fluids rich in methane and/or hydrocarbons likely altered local bulk rock carbon isotope records, but did not affect the global carbon cycle. Interestingly, Tisoa siphonalis has been described from many locations in the Grands Causses Basin in southern France, and from northern France and Luxemburg, always occurring at the same stratigraphic level. Upper Pliensbachian authigenic carbonates thus possibly cover an area of many thousand square kilometers. Greatly reduced sedimentation rates are needed to explain the stabilization of the sulfate-methane transition zone in the sedimentary column in order for the tubular concretions to form. Late Pliensbachian cooling, reducing run-off, and/or the influx of colder water and more vigorous circulation could be responsible for a halt in sedimentation. At the same time (thermogenic) methane may have destabilized during a major phase of Late Pliensbachian sea level fall. As such Tisoa siphonalis is more than a geological curiosity, and its further study could prove pivotal in understanding Early Jurassic paleoenvironmental change.

Quantitative real-time or kinetic RTPCR is increasingly used for the quantification of specific mRNA targets, especially in clinical applications. To quantify the mRNA of cytokines and their receptors, which play important roles in the pathogenesis of autoimmune diseases such as multiple sclerosis, we have developed quantitative two-step RT-PCR assays for IL-4, IL-4R, IFN-γ, IFN-β, and the housekeeping gene porphobilinogen deaminase (PBGD). The LightCyclerTM system was used to quantify the copy numbers with the sequence-specific hybridization probe detection format. The quantification was carried out on the basis of standard curves generated with external homologous plasmids for each different parameter in relation to the gene expression of PBGD. Therefore, this procedure represents a relative quantification method with external standards, as the standard curves were used to obtain an absolute value for the copy numbers of the targets and the reference (PBGD). The new software version 3.5 of the LightCycler system allows the construction of a single parameter-dependent plasmid standard curve for the quantification of unknown samples from different runs. Here we demonstrate how to achieve precise and reproducible quantification, even when using measurements from different PCR runs.