Demonstration of reduced neoclassical energy transport in Wendelstein 7-X.

Research on magnetic confinement of high-temperature plasmas has the ultimate goal of harnessing nuclear fusion for the production of electricity. Although the tokamak1 is the leading toroidal magnetic-confinement concept, it is not without shortcomings and the fusion community has therefore also pursued alternative concepts such as the stellarator. Unlike axisymmetric tokamaks, stellarators possess a three-dimensional (3D) magnetic field geometry. The availability of this additional dimension opens up an extensive configuration space for computational optimization of both the field geometry itself and the current-carrying coils that produce it. Such an optimization was undertaken in designing Wendelstein 7-X (W7-X)2, a large helical-axis advanced stellarator (HELIAS), which began operation in 2015 at Greifswald, Germany. A major drawback of 3D magnetic field geometry, however, is that it introduces a strong temperature dependence into the stellarator's non-turbulent 'neoclassical' energy transport. Indeed, such energy losses will become prohibitive in high-temperature reactor plasmas unless a strong reduction of the geometrical factor associated with this transport can be achieved; such a reduction was therefore a principal goal of the design of W7-X. In spite of the modest heating power currently available, W7-X has already been able to achieve high-temperature plasma conditions during its 2017 and 2018 experimental campaigns, producing record values of the fusion triple product for such stellarator plasmas3,4. The triple product of plasma density, ion temperature and energy confinement time is used in fusion research as a figure of merit, as it must attain a certain threshold value before net-energy-producing operation of a reactor becomes possible1,5. Here we demonstrate that such record values provide evidence for reduced neoclassical energy transport in W7-X, as the plasma profiles that produced these results could not have been obtained in stellarators lacking a comparably high level of neoclassical optimization.

[Late-life depression and frailty-Epidemiological, clinical and neurobiological associations]. / Depression im Alter und Frailty ­ epidemiologische, klinische und neurobiologische Zusammenhänge.

BACKGROUND: Depression is the most common mental disorder in older adults and is influenced by age-related processes. Frailty is a well-established clinical expression of ageing that implies a state of increased vulnerability to stressor events as well as increased risks of disability, hospitalization and death. Neurobiological findings will disentangle the comorbidity of frailty and depression and may inform future management of depression in old age. OBJECTIVE: This narrative review provides an overview of the comorbidity of late-life depression and frailty, with a focus on neuroscientific findings that are organized within the research domain criteria (RDoC) framework. RESULTS: More than one third of old people with depression are affected by frailty, which results in more chronic depression and in poorer efficacy and tolerability of antidepressant medication. Depression and frailty share motivational and psychomotor characteristics, particularly apathy, decreased physical activity and fatigue. In patients with frailty, altered activity of the supplementary motor cortex is associated with motor performance deficits. Patients with late-life depression and apathy are characterized by abnormal structure and altered functional connectivity of the reward network and the salience network, along with altered functional connectivity of these networks with premotor brain areas. CONCLUSION: Identifying frailty in older adults with depression is relevant for prognostic assessment and treatment. A better understanding of the neuronal mechanisms of comorbidity will provide potential targets for future personalized therapeutic interventions.

Impact of Magnetic Field Configuration on Heat Transport in Stellarators and Heliotrons.

We assess the magnetic field configuration in modern fusion devices by comparing experiments with the same heating power, between a stellarator and a heliotron. The key role of turbulence is evident in the optimized stellarator, while neoclassical processes largely determine the transport in the heliotron device. Gyrokinetic simulations elucidate the underlying mechanisms promoting stronger ion scale turbulence in the stellarator. Similar plasma performances in these experiments suggests that neoclassical and turbulent transport should both be optimized in next step reactor designs.

[Antipsychotic-induced motor symptoms in schizophrenic psychoses-Part 2 : Catatonic symptoms and neuroleptic malignant syndrome]. / Antipsychotikaassoziierte motorische Symptome bei schizophrenen Psychosen ­ Teil 2 : Katatone Symptome und malignes neuroleptisches Syndrom.

In rare cases, pharmacotherapy in schizophrenic psychoses can be associated with life-threatening antipsychotic-induced movement disorders. The two most severe complications are antipsychotic-associated catatonic symptoms (ACS) and neuroleptic malignant syndrome (NMS). Although both constellations necessitate rapid medical care, the diagnosis is still a clinical challenge. Although there is no established treatment of ACS (here designated as a specific subtype of catatonic symptoms), an attempt should be made with benzodiazepines and memantine can also be helpful. In severe drug-refractory cases electroconvulsive therapy (ECT) can be indicated. The NMS represents a life-threatening constellation that frequently requires intensive care unit treatment. The medicinal treatment with benzodiazepines, bromocriptine, amantadine, dantrolene and/or ECT is also advocated. Finally, this review article also summarizes the currently available literature for treatment of genuine catatonic symptoms. In conclusion, the abovementioned clinical syndromes must be rapidly recognized and treated. Early recognition and treatment of these movement disorders can under certain circumstances be lifesaving and favorably influence the later clinical outcome.

[Antipsychotic-induced motor symptoms in schizophrenic psychoses-Part 3 : Tardive dyskinesia]. / Antipsychotikaassoziierte motorische Symptome bei schizophrenen Psychosen ­ Teil 3 : Spätdyskinesien.

The treatment of schizophrenic psychoses with antipsychotic drugs (AP) is often associated with an increased risk of delayed occurrence of antipsychotic-associated movement disorders. Persistence and chronicity of such symptoms are very frequent. The risk of developing tardive dyskinesia (TD) is associated with the pharmacological effect profile of a particular AP, with treatment duration and age. This systematic review article summarizes the current study situation on prevalence, risk factors, prevention and treatment options and instruments for early prediction of TD in schizophrenic psychoses. The current data situation on treatment strategies for TD is very heterogeneous. For the treatment of TD there is preliminary evidence for reduction or discontinuation of the AP, switching to clozapine, administration of benzodiazepines (clonazepam) and treatment with vesicular monoamine transporter (VMAT2) inhibitors, ginkgo biloba, amantadine or vitamin E. Although TD can be precisely diagnosed it cannot always be effectively treated. Early detection and early treatment of TD can have a favorable influence on the prognosis and the clinical outcome.

[Antipsychotic-induced motor symptoms in schizophrenic psychoses-Part 1 : Dystonia, akathisia und parkinsonism]. / Antipsychotikaassoziierte motorische Symptome bei schizophrenen Psychosen ­ Teil 1 : Dystonien, Akathisie und Parkinsonismus.

Acute antipsychotic-induced movement disorders (AIMD) are clinically relevant since they are frequently associated with high subjective distress, and since over the long-term they can negatively impact treatment adherence of patients with schizophrenic psychoses. This review article summarizes the relevant studies on the prevalence, risk factors, prevention and treatment options and instruments for early prediction of acute AIMD in schizophrenic psychoses. The current evidence and treatment recommendations are divided into three main areas: acute dystonia, akathisia, and parkinsonism. For the treatment of acute dystonia trihexyphenidyl and biperiden have shown their efficacy. Considering pharmacological treatment of akathisia, there is some preliminary evidence for medication with lipophilic beta-receptor blockers (propranolol and pindolol), clonidine, benzodiazepines, mianserin, mirtazapine und trazodone. The treatment options for drug-induced parkinsonism include reduction or switching from one antipsychotic to another with a lower affinity for dopamine D2 receptors, amantadine or in the regular administration of anticholinergic drugs. In conclusion, acute AIMD is easily to recognize but is not always effectively and durably treated. Early recognition and treatment of acute AIMD could be associated with improved treatment outcomes.

[Genuine motor phenomena in schizophrenic psychoses : Theoretical background and definition of context]. / Genuine motorische Phänomene bei schizophrenen Psychosen : Theoretischer Hintergrund und Kontextdefinition.

Besides positive and negative symptoms, motor abnormalities have been increasingly recognized as central symptoms of schizophrenia. Recent investigations of antipsychotic-naive first-episode patients with schizophrenia found significantly higher rates of genuine motor abnormalities (GMA) when compared to healthy individuals. The first part of this article introduces the historical and clinical background of GMA in schizophrenia. In the second part the relevance of scientific research and clinical implication of GMA in schizophrenia are discussed. Finally, this article aims at presenting a conceptual framework and a reference system involving both genuine and drug-induced motor abnormalities. The future clinical implications of GMA research are presented and multimodal and transdiagnostic studies are advocated. Future research on GMA will not only essentially enrich the formation of psychiatric theories but also promote progress in clinical neuroscience.

[Genuine motor phenomena in schizophrenia : Neuronal correlates and pathomechanisms]. / Genuine motorische Phänomene bei schizophrenen Psychosen : Neuronale Korrelate und Pathomechanismen.

Despite a growing body of evidence on motor dysfunction in schizophrenia spectrum disorders, the neuronal correlates of genuine motor abnormalities (GMA) are not fully elucidated at present. Moreover, the clinical relevance of a potential "motor intermediate phenotype" remains controversial. This systematic review aims at characterizing a "motor intermediate phenotype" in schizophrenia spectrum disorders. The second goal of this systematic review is to discuss GMA-associated brain alterations as potential biomarkers of psychosis risk syndrome and manifest motor symptoms against the background of current neuroimaging evidence. The detailed clinical assessment of GMA in the context of multimodal imaging could, in the future promote the early recognition of psychotic disorders and the initiation of disorder-oriented and individualized treatment. Taken as a whole the data provide initial evidence that motor dysfunction in schizophrenic spectrum disorders must be considered dimensionally. The predictive value of neurobiological results with respect to the transition to a life-threatening catatonia or the development of chronic dyskinesia, cannot currently be conclusively assessed.

[German version of the Northoff catatonia rating scale (NCRS-dv) : A validated instrument for measuring catatonic symptoms]. / Deutsche Version der Northoff Catatonia Rating Scale (NCRS-dv) : Ein validiertes Messinstrument zur Erfassung katatoner Symptome.

The clinical picture of catatonia includes impressive motor phenomena, such as rigidity, dyskinesia, festination, negativism, posturing, catalepsy, stereotypies and mannerisms, along with affective (e. g. aggression, anxiety, anhedonism or emotional lability) and behavioral symptoms (e.g. mutism, autism, excitement, echolalia or echopraxia). In English speaking countries seven catatonia rating scales have been introduced, which are widely used in clinical and scientific practice. In contrast, only one validated catatonia rating scale is available in Germany so far. In this paper, we introduce the German version of the Northoff catatonia rating scale (NCRS-dv). The original English version of the NCRS consists of 40 items describing motor (13 items), affective (12 items) and behavioral (15 items) catatonic symptoms. The NCRS shows high internal reliability (Crombachs alpha = 0.87), high interrater (r = 0.80-0.96) and high intrarater (r = 0.80-0.95) reliability. Factor analysis of the NCRS revealed four domains: affective, hyperactive or excited, hypoactive or retarded and behavior with individual eigenvalues of 8.98, 3.61, 2.98 and 2.82, respectively, which explained 21.5 %, 9.3 %, 7.6 % and 7.2 % of variance, respectively. In conclusion, the NCRS-dv represents a second validated instrument which can be used by German clinicians and scientists for the assessment of catatonic symptoms.

Voriconazole exposure and the risk of cutaneous squamous cell carcinoma in allogeneic hematopoietic stem cell transplant patients.

BACKGROUND: Voriconazole is a commonly used antifungal medication in allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients. In solid organ transplantation, voriconazole use has been associated with the development of cutaneous squamous cell carcinoma (SCC). We sought to determine if voriconazole use was associated with SCC in patients undergoing allo-HSCT. METHODS: We retrospectively reviewed consecutive adult patients who underwent allo-HSCT at Mayo Clinic from January 2007 through July 2012. Multivariable Cox models were created to assess the relationship of SCC with two time-dependent voriconazole exposure variables: (i) history of voriconazole exposure (yes/no), and (ii) cumulative days of voriconazole use. RESULTS: In our cohort of 381 allo-HSCT patients, SCC developed in 26 of 312 patients exposed to voriconazole (25 post-voriconazole) and in 1 of 69 patients who received alternative antifungal agent(s). Cumulative incidence of SCC was estimated to be 19% at 5 years post allo-transplant. Cumulative days of voriconazole use was found to be a risk factor for SCC, and this relationship persisted in a multivariable model using previously identified risk factors as covariates (hazard ratio 1.859 for each 180 days of use, P < 0.001). CONCLUSION: This is the first study, to our knowledge, to identify cumulative days of voriconazole use as a risk factor for SCC development following allo-HSCT, and may help guide appropriate antifungal use in this patient population.

Revisiting default mode network function in major depression: evidence for disrupted subsystem connectivity.

BACKGROUND: Major depressive disorder (MDD) is characterized by alterations in brain function that are identifiable also during the brain's 'resting state'. One functional network that is disrupted in this disorder is the default mode network (DMN), a set of large-scale connected brain regions that oscillate with low-frequency fluctuations and are more active during rest relative to a goal-directed task. Recent studies support the idea that the DMN is not a unitary system, but rather is composed of smaller and distinct functional subsystems that interact with each other. The functional relevance of these subsystems in depression, however, is unclear. METHOD: Here, we investigated the functional connectivity of distinct DMN subsystems and their interplay in depression using resting-state functional magnetic resonance imaging. RESULTS: We show that patients with MDD exhibit increased within-network connectivity in posterior, ventral and core DMN subsystems along with reduced interplay from the anterior to the ventral DMN subsystems. CONCLUSIONS: These data suggest that MDD is characterized by alterations of subsystems within the DMN as well as of their interactions. Our findings highlight a critical role of DMN circuitry in the pathophysiology of MDD, thus suggesting these subsystems as potential therapeutic targets.

Abnormal resting-state connectivity of motor and cognitive networks in early manifest Huntington's disease.

BACKGROUND: Functional magnetic resonance imaging (fMRI) of multiple neural networks during the brain's 'resting state' could facilitate biomarker development in patients with Huntington's disease (HD) and may provide new insights into the relationship between neural dysfunction and clinical symptoms. To date, however, very few studies have examined the functional integrity of multiple resting state networks (RSNs) in manifest HD, and even less is known about whether concomitant brain atrophy affects neural activity in patients. METHOD: Using MRI, we investigated brain structure and RSN function in patients with early HD (n = 20) and healthy controls (n = 20). For resting-state fMRI data a group-independent component analysis identified spatiotemporally distinct patterns of motor and prefrontal RSNs of interest. We used voxel-based morphometry to assess regional brain atrophy, and 'biological parametric mapping' analyses to investigate the impact of atrophy on neural activity. RESULTS: Compared with controls, patients showed connectivity changes within distinct neural systems including lateral prefrontal, supplementary motor, thalamic, cingulate, temporal and parietal regions. In patients, supplementary motor area and cingulate cortex connectivity indices were associated with measures of motor function, whereas lateral prefrontal connectivity was associated with cognition. CONCLUSIONS: This study provides evidence for aberrant connectivity of RSNs associated with motor function and cognition in early manifest HD when controlling for brain atrophy. This suggests clinically relevant changes of RSN activity in the presence of HD-associated cortical and subcortical structural abnormalities.

The neuroanatomy of subthreshold depressive symptoms in Huntington's disease: a combined diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) study.

BACKGROUND: Depressive symptoms are prominent psychopathological features of Huntington's disease (HD), making a negative impact on social functioning and well-being. METHOD: We compared the frequencies of a history of depression, previous suicide attempts and current subthreshold depression between 61 early-stage HD participants and 40 matched controls. The HD group was then split based on the overall HD group's median Hospital Anxiety and Depression Scale-depression score into a group of 30 non-depressed participants (mean 0.8, s.d. = 0.7) and a group of 31 participants with subthreshold depressive symptoms (mean 7.3, s.d. = 3.5) to explore the neuroanatomy underlying subthreshold depressive symptoms in HD using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). RESULTS: Frequencies of history of depression, previous suicide attempts or current subthreshold depressive symptoms were higher in HD than in controls. The severity of current depressive symptoms was also higher in HD, but not associated with the severity of HD motor signs or disease burden. Compared with the non-depressed HD group DTI revealed lower fractional anisotropy (FA) values in the frontal cortex, anterior cingulate cortex, insula and cerebellum of the HD group with subthreshold depressive symptoms. In contrast, VBM measures were similar in both HD groups. A history of depression, the severity of HD motor signs or disease burden did not correlate with FA values of these regions. CONCLUSIONS: Current subthreshold depressive symptoms in early HD are associated with microstructural changes - without concomitant brain volume loss - in brain regions known to be involved in major depressive disorder, but not those typically associated with HD pathology.

[Electroconvulsive therapy in depression: insights from fMRI, PET and SPECT studies]. / Elektrokonvulsive Therapie bei Depression: Welche Erkenntnisse erbringen fMRT-, PET- und SPECT-Untersuchungen?

Electroconvulsive therapy (ECT) is the most potent and rapidly acting of all antidepressant treatments in major depressive disorder (MDD). Nuclear and functional magnetic (fMRI) brain imaging studies of ECT have substantially contributed to the neurobiological understanding of this treatment modality. Neuroimaging methods may also validate potential mechanisms of antidepressant action. Models of neural dysfunction in MDD suggest impaired modulation of activity within a cortico-limbic circuitry, along with alterations in the functional organisation of multiple brain networks implicated in emotional processes. Nuclear imaging techniques have demonstrated consistent patterns of ECT-induced ictal changes in brain activity that appear to be linked to efficacy and side effects of ECT. Interictally, widespread alterations of brain function have been reported, however, results remain inconclusive. FMRI studies of ECT have demonstrated longer-lasting, interictal changes of neural activity in multiple cerebral regions that are in accordance with functional neuroanatomical models of mood disorders. Future research detailing ECT interactions with brain pathophysiology in MDD could potentially provide a clinically useful framework to better predict ECT treatment response and/or side effects, and may also facilitate the development of more focused brain stimulation techniques.

Sources for constellation errors in modulated dispersion interferometers.

Dispersion interferometry (DI) is being employed on an increasing number of fusion experiments to measure the plasma density with a minimal sensitivity to vibrations. DIs employed in high-density experiments use phase modulation techniques up to several hundred kilohertz to enable quadrature detection and to be unaffected by variations of the signal amplitude. However, the evaluation of the temporal interferogram can be a significant source for phase errors and does not have an established processing method. There are two non-approximation-based methods currently in use: one using the ratio of amplitudes in the signal's Fourier spectrum and the other using its sectioned integration. Previously, the methods could not be used simultaneously since they differ in their respective calibration point. In this paper, we present a technique to use both phase evaluation methods simultaneously using quadrature correction methods. A comparison of their strengths and weaknesses is presented based on identical measurements indicating one to be more reliable in a more static measurement scenario, while the other excels in highly dynamic ones. Several comparative experiments are presented, which identify a significant error source in the phase measurement induced by polarization rotation. Since the same effect may be induced by Faraday rotation, the results may have direct consequence on the design of the ITER dispersion interferometer/polarimeter as well as the European DEMO's interferometer concept.

Quality of life after restorative proctocolectomy and ileal pouch-anal anastomosis in patients with familial adenomatous polyposis: a matter of adjustment.

AIM: Favourable outcomes for health-related quality of life (HRQL) have been reported in patients with familial adenomatous polyposis (FAP) after restorative proctocolectomy and ileal pouch-anal anastomosis (RPC). However, less is known about patients' subjective experience and adjustment to postoperative impairment. Using a multidimensional psychometric assessment, we investigated patient-reported HRQL to determine the impact of the patient's subjective experience together with medical, functional and psychosocial factors on HRQL. METHOD: In this cross-sectional study, 116 FAP patients who had undergone RPC on average 8 years earlier completed standardized and study-specific questionnaires and participated in a personal interview. The impact of medical, functional and psychosocial factors on patients' HRQL was determined by regression analyses. RESULTS: When using a generic psychometric measure, FAP patients' overall HRQL was comparable with that of the general population. Impaired HRQL, however, was found in patients reporting poor pouch function in contrast to those reporting good or moderate functional outcome. Findings from a personalized interview also suggested that a good functional result does not necessarily translate into good HRQL. Personal resources predicted patients' physical and psychological well-being, whereas little variance of HRQL was explained by medical factors and function. CONCLUSION: Patients' HRQL is, to a substantial degree, the result of adjustment to the adverse impact of RPC. By using personal resources the majority of patients may achieve satisfactory HRQL levels even when bowel function is impaired. A multidimensional assessment that comprises medical, functional and psychosocial aspects is required to ascertain an adequate evaluation of FAP patients after RPC.

[Pharmacotherapeutic treatment strategies for smoking cessation]. / Pharmakologische Strategien zur Unterstützung einer Raucherentwöhnung.

Regular tobacco smoking occurs in about 35% of the male and 25% of the female German population. Individual attempts to independently quit smoking and to remain abstinent for 1 year have been shown to be successful in less than 5% of cases. This rate can be doubled by means of individual consulting and cognitive-behavioral interventions and additional pharmacological treatment might increase abstinence rates up to 25%. Apart from nicotine substitution (e.g. transdermal, oral and inhalative applications) and bupropion, recent studies have shown beneficial effects of varenicline for smoking cessation and abstinence. Varenicline, a selective partial nicotinergic agonist, has been specifically developed for the purpose of smoking cessation. Currently available data suggest that varenicline is more effective compared to nicotine substitution therapy and bupropion, increasing the abstinence likelihood by a factor of 2.3 compared to a placebo. Recent data regarding anti-nicotine vaccines suggest that this approach might yield a comparable treatment outcome and probably even better relapse-preventing effects than conventional psychopharmacological strategies. The first anti-nicotine vaccines are expected to be approved by national authorities within the forthcoming 1-2 years.

Neural network surrogates of Bayesian diagnostic models for fast inference of plasma parameters.

We present a framework for training artificial neural networks (ANNs) as surrogate Bayesian models for the inference of plasma parameters from diagnostic data collected at nuclear fusion experiments, with the purpose of providing a fast approximation of conventional Bayesian inference. Because of the complexity of the models involved, conventional Bayesian inference can require tens of minutes for analyzing one single measurement, while hundreds of thousands can be collected during a single plasma discharge. The ANN surrogates can reduce the analysis time down to tens/hundreds of microseconds per single measurement. The core idea is to generate the training data by sampling them from the joint probability distribution of the parameters and observations of the original Bayesian model. The network can be trained to learn the reconstruction of plasma parameters from observations and the model joint probability distribution from plasma parameters and observations. Previous work has validated the application of such a framework to the former case at the Wendelstein 7-X and Joint European Torus experiments. Here, we first give a description of the general methodological principles allowing us to generate the training data, and then we show an example application of the reconstruction of the joint probability distribution of an effective ion charge Zeff-bremsstrahlung model from data collected at the latest W7-X experimental campaign. One key feature of such an approach is that the network is trained exclusively on data generated with the Bayesian model, requiring no experimental data. This allows us to replicate the training scheme and generate fast, surrogate ANNs for any validated Bayesian diagnostic model.

Vasogenic Brain Edema During Maintenance Hemodialysis : Preliminary Results from Tract-based Spatial Statistics and Voxel-based Morphometry.

BACKGROUND: Hemodialysis (HD), especially when first initiated, can cause neurological deterioration. Presumably this is due to transient cerebral edema, which has been observed using diffusion weighted magnetic resonance imaging (MRI) in experimental and human studies; however, this has not been investigated under maintenance hemodialysis (mHD). Moreover, there are no studies to date investigating regional effects of mHD on grey and white matter volumes. METHODS: In this study eight patients with end stage renal disease (ESRD) were examined immediately before and after mHD sessions with multimodal MRI, including diffusion tensor imaging (DTI) and high-resolution structural imaging. Additionally, eight healthy, age-matched and sex-matched controls were examined for comparison. Data were analyzed using tract-based spatial statistics and voxel-based morphometry. RESULTS: At baseline, ESRD patients had significantly reduced values of fractional anisotropy (FA) and axial diffusivity as well as bilaterally reduced grey matter volume in the insula, compared with controls. After the mHD session, FA further decreased while axial, radial, and mean diffusivity significantly increased ubiquitously throughout the white matter. Voxel-based morphometry revealed a corresponding significant increase in white matter volume in the central right hemisphere and splenium, as well as in cortical grey matter in the anterior medial frontal and cingulate cortex. None of the patients showed neurological deterioration. CONCLUSION: In this study ESRD patients showed white matter changes indicative of chronic microstructural damage when compared with healthy controls, as previously reported. In addition, patients showed signs of a transient extracellular cerebral edema, which has not yet been observed in the absence of neurological symptoms.