84 research outputs found

    The ADEBAR project: European and international provision of analytical data from structure elucidation and analytical characterization of NPS.

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    Novel substances for which none or limited analytical data are available constitute a challenge for police and customs forensic laboratories. The time-consuming process of structural elucidation and acquisition of analytical data has been centralized in the ADEBAR project in Germany, co-funded since 2017 by the EU's Internal Security Fund. The project aims to comprehensively characterize substances relevant for forensic-toxicological casework within the analytical competence network. The analytical datasets are distributed digitally through European and (inter)national channels. Additionally, pharmacological evaluation allows for estimating in vivo potency and potential harm required as scientific evidence for legislative amendments. The ADEBAR project contributes to the availability of analytical data on new substances relevant to the daily work of police and customs laboratories. Since the inception of the ADEBAR project, 549 samples have been registered, and 302 substance reports notified to the EMCDDA, including numerous spectrometric and spectroscopic data. In addition, 3,619 mass spectra have been accumulated in ADEBAR mass spectra databases. A central institution for the structure elucidation and acquisition of valid, high-quality analytical data for police and customs forensic laboratories and forensic medicine institutes is important in the future because there does not seem to be an end to the dynamic of novel NPS appearing on the drug market

    A Statistical Model to Assess Risk for Supporting COVID-19 Quarantine Decisions

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    In Germany, local health departments are responsible for surveillance of the current pandemic situation. One of their major tasks is to monitor infected persons. For instance, the direct contacts of infectious persons at group meetings have to be traced and potentially quarantined. Such quarantine requirements may be revoked, when all contact persons obtain a negative polymerase chain reaction (PCR) test result. However, contact tracing and testing is time-consuming, costly and not always feasible. In this work, we present a statistical model for the probability that no transmission of COVID-19 occurred given an arbitrary number of negative test results among contact persons. Hereby, the time-dependent sensitivity and specificity of the PCR test are taken into account. We employ a parametric Bayesian model which combines an adaptable Beta-Binomial prior and two likelihood components in a novel fashion. This is illustrated for group events in German school classes. The first evaluation on a real-world dataset showed that our approach can support important quarantine decisions with the goal to achieve a better balance between necessary containment of the pandemic and preservation of social and economic life. Future work will focus on further refinement and evaluation of quarantine decisions based on our statistical model

    Monogenic variants in dystonia: an exome-wide sequencing study

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    Background Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. Methods For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow. Findings We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism. Interpretation In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations

    Die Effekte interozeptiver ExpositionsĂŒbungen in der Kognitiven Verhaltenstherapie von Panikstörung mit Agoraphobie

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    Hintergrund: In der Kognitiven Verhaltenstherapie (KVT) der Panikstörung mit Agoraphobie (PD/AG) werden hĂ€ufig KörperĂŒbungen zur Symptomprovokation (interozeptive Exposition) eingesetzt, jedoch liegen kaum systematische, empirische Untersuchungen zu Wirkung und Wirkweise dieser Übungen vor. Ziel der vorliegenden Studie war die Charakterisierung individueller Reaktionen auf interozeptive Übungen sowie die mit der Wiederholung der Übungen verbundenen VerĂ€nderungen dieser Reaktionen. Patienten und Methoden: Selbstberichtdaten zu ausgelösten Körpersymptomen sowie Symptom- und AngststĂ€rken von 301 Patienten mit PD/AG, die verschiedene interozeptive Übungen durchfĂŒhrten, wurden ausgewertet. Die DurchfĂŒhrung der interozeptiven Exposition erfolgte im Rahmen einer manualisierten KVT des Psychotherapieverbundes «Panik-Netz». Ergebnisse: Interozeptive Exposition löste Körpersymptome und damit verbunden Angst aus. Am hĂ€ufigsten wurden vestibulĂ€re, respiratorische und kardiovaskulĂ€re Symptome ausgelöst. Die stĂ€rkste SymptomausprĂ€gung verbunden mit der stĂ€rksten Angst erzeugten die Übungen «Drehen», «Hyperventilieren» und «Strohhalmatmung». Übungswiederholung bewirkte eine Reduktion der Symptom- und AngststĂ€rken, insbesondere die Übungen «Drehen», «Strohhalmatmung» und «Hyperventilieren». Diskussion und Schlussfolgerungen: Interozeptive Exposition ist gut geeignet zur Auslösung von Körpersymptomen und zur Reduktion der damit verbundenen Symptom- und AngststĂ€rke, insbesondere ĂŒber die Übungen «Drehen», «Hyperventilieren» und «Strohhalmatmung». Zur grĂ¶ĂŸeren Angst- und SymptomstĂ€rkenreduktion empfiehlt sich eine hohe Wiederholungsrate. Die Relevanz respiratorischer, vestibulĂ€rer und kardiovaskulĂ€rer Symptome fĂŒr den Behandlungserfolg sollte weiterfĂŒhrend untersucht werden.Background: Although interoceptive exposure is a frequent component of cognitive-behavioral therapies (CBT) in panic disorder with agoraphobia, there is a lack of evidence investigating the effect of this treatment component and its underlying mechanisms of change. The present study aimed at characterizing individual responses to interoceptive exposure and response changes after repeated exposure. Patients and Methods: Under the national research initiative ‘Panic Net’, self-report data were analyzed including bodily symptoms, symptom intensity and experienced anxiety during interoceptive exposure of 301 PD/AG patients who participated in a manualized CBT trial. Results: Interoceptive exposure induced bodily symptoms and anxiety. Respiratory, vestibular and cardiovascular symptoms were most frequently reported. Spinning, breathing through a straw and hyperventilation produced most intense symptom reports and anxiety ratings. Repeating the interoceptive exposure reliably reduced reported symptom intensity and anxiety ratings particularly after spinning, breathing through a straw and hyperventilation. Discussion and Conclusions: In PD/AG patients, interoceptive exposure induces bodily symptoms and reduces reported symptom intensity and anxiety, particularly through spinning, hyperventilation and breathing through a straw. Repeated rehearsal is encouraged given that larger reduction of anxiety and symptom reports were associated with more training. Further research is needed to assess the relevance of respiratory, vestibular and cardiovascular symptoms for CBT treatment

    The structural features of Acetobacterium woodii F‐ATP synthase reveal the importance of the unique subunit γ‐loop in Na+ translocation and ATP synthesis

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    The Na+translocating F1FO ATP synthase from Acetobacterium woodii shows a subunit stoichiometry of α3:ÎČ3:Îł:ÎŽ:Δ:a:b2:(c2/3)9:c1 and reveals an evolutionary path between synthases and pumps involving adaptations in the rotor c‐ring, which is composed of F‐ and vacuolar‐type c subunits in a stoichiometry of 9 : 1. This hybrid turbine couples rotation with Na+ translocation in the FO part and rotation of the central stalk subunits γ‐Δ to drive ATP synthesis in the catalytic α3:ÎČ3 headpiece. Here, we isolated a highly pure recombinant A. woodii F‐ATP synthase and present the first projected structure of this hybrid engine as determined by negative‐stain electron microscopy and single‐particle analysis. The uniqueness of the A. woodii F‐ATP synthase is also reflected by an extra 17 amino acid residues loop (195TSGKVKITEETKEEKSK211) in subunit Îł. Deleting the loop‐encoding DNA sequence (γΔ195–211) and purifying the recombinant F‐ATP synthase γΔ195–211 mutant provided a platform to study its effect in enzyme stability and activity. The recombinant F‐ATP synthase γΔ195–211 mutant revealed the same subunit composition as the wild‐type enzyme and a minor reduction in ATP hydrolysis. When reconstituted into proteoliposomes ATP synthesis and Na+ transport were diminished, demonstrating the importance of the Îł195–211 loop in both enzymatic processes. Based on a structural model, a coupling mechanism for this enzyme is proposed, highlighting the role of the γ‐loop. Finally, the Îł195–211 loop of A. woodii is discussed in comparison with the extra γ‐loops of mycobacterial and chloroplasts F‐ATP synthases described to be involved in species‐specific regulatory mechanisms.NRF (Natl Research Foundation, S’pore)Accepted versio

    Support Vector Machine Analysis of Functional Magnetic Resonance Imaging of Interoception Does Not Reliably Predict Individual Outcomes of Cognitive Behavioral Therapy in Panic Disorder with Agoraphobia

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    BACKGROUND: The approach to apply multivariate pattern analyses based on neuro imaging data for outcome prediction holds out the prospect to improve therapeutic decisions in mental disorders. Patients suffering from panic disorder with agoraphobia (PD/AG) often exhibit an increased perception of bodily sensations. The purpose of this investigation was to assess whether multivariate classification applied to a functional magnetic resonance imaging (fMRI) interoception paradigm can predict individual responses to cognitive behavioral therapy (CBT) in PD/AG. METHODS: This analysis is based on pretreatment fMRI data during an interoceptive challenge from a multicenter trial of the German PANIC-NET. Patients with DSM-IV PD/AG were dichotomized as responders (n = 30) or non-responders (n = 29) based on the primary outcome (Hamilton Anxiety Scale Reduction ≄50%) after 6 weeks of CBT (2 h/week). fMRI parametric maps were used as features for response classification with linear support vector machines (SVM) with or without automated feature selection. Predictive accuracies were assessed using cross validation and permutation testing. The influence of methodological parameters and the predictive ability for specific interoception-related symptom reduction were further evaluated. RESULTS: SVM did not reach sufficient overall predictive accuracies (38.0–54.2%) for anxiety reduction in the primary outcome. In the exploratory analyses, better accuracies (66.7%) were achieved for predicting interoception-specific symptom relief as an alternative outcome domain. Subtle information regarding this alternative response criterion but not the primary outcome was revealed by post hoc univariate comparisons. CONCLUSION: In contrast to reports on other neurofunctional probes, SVM based on an interoception paradigm was not able to reliably predict individual response to CBT. Results speak against the clinical applicability of this technique

    DNA methylation-based classification of central nervous system tumours

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    Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challengingwith substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology

    The Rnf complex is an energy-coupled transhydrogenase essential to reversibly link cellular NADH and ferredoxin pools in the acetogen acetobacterium woodii

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    © 2018 American Society for Microbiology. The Rnf complex is a respiratory enzyme that catalyzes the oxidation of reduced ferredoxin to the reduction of NAD + , and the negative free energy change of this reaction is used to generate a transmembrane ion gradient. In one class of anaerobic acetogenic bacteria, the Rnf complex is believed to be essential for energy conservation and autotrophic growth. We describe here a methodology for markerless mutagenesis in the model bacterium of this class, Acetobacterium woodii, which enabled us to delete the rnf genes and to test their in vivo role. The rnf mutant did not grow on H 2 plus CO 2 , nor did it produce acetate or ATP from H 2 plus CO 2 , and ferredoxin:NAD + oxidoreductase activity and Na + translocation were also completely lost, supporting the hypothesis that the Rnf complex is the only respiratory enzyme in this metabolism. Unexpectedly, the mutant also did not grow on low-energy substrates, such as ethanol or lactate. Oxidation of these substrates is not coupled to the reduction of ferredoxin but only of NAD + , and we speculated that the growth phenotype is caused by a loss of reduced ferredoxin, indispensable for biosynthesis and CO 2 reduction. The electron-bifurcating hydrogenase of A. woodii reduces ferredoxin, and indeed, the addition of H 2 to the cultures restored growth on ethanol and lactate. This is consistent with the hypothesis that endergonic reduction of ferredoxin with NADH is driven by reverse electron transport catalyzed by the Rnf complex, which renders the Rnf complex essential also for growth on low-energy substrates. IMPORTANCE Ferredoxin and NAD + are key electron carriers in anaerobic bacteria, but energetically, they are not equivalent, since the redox potential of ferredoxin is lower than that of the NADH/NAD + couple. We describe by mutant studies in Acetobacterium woodii that the main function of Rnf is to energetically link cellular pools of ferredoxin and NAD + . When ferredoxin is greater than NADH, exergonic electron flow from ferredoxin to NAD + generates a chemiosmotic potential. This is essential for energy conservation during autotrophic growth. When NADH is greater than ferredoxin, Rnf works in reverse. This reaction is essential for growth on low-energy substrates to provide reduced ferredoxin, indispensable for biosynthesis and CO 2 reduction. Our studies put a new perspective on the cellular function of the membrane-bound ion-translocating Rnf complex widespread in bacteria

    Comparing two different arginine vasopressin doses in advanced vasodilatory shock: a randomized, controlled, open-label trial

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    Purpose: To compare the effects of two arginine vasopressin (AVP) dose regimens on the hemodynamic response, catecholamine requirements, AVP plasma concentrations, organ function and adverse events in advanced vasodilatory shock. Methods: In this prospective, controlled, open-label trial, patients with vasodilatory shock due to sepsis, systemic inflammatory response syndrome or after cardiac surgery requiring norepinephrine >0.6ÎŒg/kg/min were randomized to receive a supplementary AVP infusion either at 0.033IU/min (n=25) or 0.067IU/min (n=25). The hemodynamic response, catecholamine doses, laboratory and organ function variables as well as adverse events (decrease in cardiac index or platelet count, increase in liver enzymes or bilirubin) were recorded before, 1, 12, 24 and 48h after randomization. A linear mixed effects model was used for statistical analysis in order to account for drop-outs during the observation period. Results: Heart rate and norepinephrine requirements decreased while MAP increased in both groups. Patients receiving AVP at 0.067IU/min required less norepinephrine (P=0.006) than those infused with AVP at 0.033IU/min. Arterial lactate and base deficit decreased while arterial pH increased in both groups. During the observation period, AVP plasma levels increased in both groups (both P<0.001), but were higher in the 0.067IU/min group (P<0.001) and in patients on concomitant hydrocortisone. The rate of adverse events and intensive care unit mortality was comparable between groups (0.033IU/min, 52%; 0.067IU/min, 52%; P=1). Conclusions: A supplementary AVP infusion of 0.067IU/min restores cardiovascular function in patients with advanced vasodilatory shock more effectively than AVP at 0.033IU/mi