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Bebilderte Multiple-Choice- (MC) Fragen sind ein integraler Bestandteil von schriftlichen Prüfungen in der Anatomie. In bebilderten MC-Fragen bezieht sich die schriftliche Frage auf verschiedene Typen von Abbildungen wie Röntgenaufnahmen, Mikrofotografien von histologischen Schnitten oder Zeichnungen von anatomischen Strukturen. Da das Hereinnehmen von Abbildungen in MC-Fragen das Abschneiden der Items beeinflussen kann, verglichen wir die Charakteristika von anatomischen Items getestet mit bebilderten und nicht bebilderten MC-Fragen in sieben Anatomieklausuren und in zwei schriftlichen Teilen des Ersten Abschnitts der Ärztlichen Prüfung (M1).
In dieser Studie verglichen wir 25 bebilderte und 163 nicht bebilderte MC-Fragen aus Anatomieklausuren und 27 bebilderte und 130 nicht bebilderte MC-Fragen aus dem schriftlichen Teil des M1 mit einem nicht parametrischen Test für ungepaarte Stichproben. Als Ergebnis waren keine signifikanten Unterschiede im Schwierigkeits- und Trennschärfeniveau zwischen bebilderten und nicht bebilderten MC-Fragen vorhanden, dasselbe ergab sich in einer nach MC-Frageformaten stratifizierten Analyse.
Wir schließen daraus, dass das bebilderte Itemformat für sich die Itemschwierigkeit nicht zu beeinflussen scheint. Die aktuellen Ergebnisse stimmen mit früheren retrospektiven Studien überein, die keine signifikanten Unterschiede zwischen Test- und Itemcharakteristika zwischen bebilderten und nicht bebilderten MC-Fragen zeigten.
Illustrated Multiple-choice questions (iMCQs) form an integral part of written tests in anatomy. In iMCQs, the written question refers to various types of figures, e. g. X-ray images, micrographs of histological sections, or drawings of anatomical structures. Since the inclusion of images in MCQs might affect item performance we compared characteristics of anatomical items tested with iMCQs and non-iMCQs in seven tests of anatomy courses and in two written parts of the first section of the German Medical Licensing Examination (M1).
In summary, we compared 25 iMCQs and 163 non-iMCQs from anatomy courses, and 27 iMCQs and 130 non-iMCQs from the written part of the M1 using a nonparametric test for unpaired samples. As a result, there were no significant differences in difficulty and discrimination levels between iMCQs and non-iMCQs, the same applied to an analysis stratified for MCQ formats.
We conclude that the illustrated item format by itself does not seem to affect item difficulty. The present results are consistent with previous retrospective studies which showed no significant differences of test or item characteristics between iMCQs and non-iMCQs.
Einleitung: Um junge Medizinstudierende auf die stetig wachsenden Anforderungen eines Arztes klinisch, wissenschaftlich sowie psycho-sozial allumfassend und kompetent besser vorzubereiten, sollten Universitäten eine enge, persönliche Erfahrungs- und Wissensvermittlung ermöglichen. Strukturierte Mentorenprogramme als Lösungsmodell klinische Aufgabenfelder früher in die vorklinische Lehre einfließen zu lassen, um somit eine begleitete Priorisierung des breiten, theoretisch geprägten universitären Lehrstoffes zu erleichtern, stellen einen vielversprechenden Ansatzpunkt dar.
Hier berichten wir über die Erfahrungen und Ergebnisse des vorklinischen Mentorenprogrammes der Universität Bonn, welches zum Wintersemester 12/13 eingeführt wurde.
Projektbeschreibung: Das Programm zeichnet sich durch das Konzept des peer-to-peer-Teachings in den Semestern der Vorklinik im Rahmen eines humanmedizinischen Regelstudienganges aus. In regelmäßigen, freiwilligen Kurstreffen mit verschiedenen klinischen Fallbeispielen soll Studierenden die Möglichkeit geboten werden, erworbene Kenntnisse aus den curricularen Grundlagenfächern eigenständig anzuwenden, sowie einen Kontakt mit einem persönlichen Ansprechpartner für Ratschläge und Hilfestellung zu gewährleisten. Auf diese Weise wird ein ungezwungener Erfahrungsaustausch ermöglicht, der den Studierenden eine Motivations- und Lernhilfe bietet, insbesondere für die mündliche Physikumsprüfung sowie für weitere Prüfungen des Studiums.
Ergebnisse: Über die letzten drei Jahre konnte die Teilnehmerzahl und das Interesse am Programm stetig gesteigert werden. Die Auswertung der gesammelten Evaluationen bestätigt eine sehr gute Kommunikation zwischen Tutor und Studierenden (über 80%), sowie durchweg gute bis sehr gute Qualität und Nützlichkeit der fachlichen, als auch sonstigen Tipps der Mentoren. Eine abschließende Bewertung der Erwartungen an das Mentorenprogramm wurde insgesamt auf einer Schulnotenskala stets als gut bis sehr gut bewertet (Wintersemester: sehr gut 64.8±5.0%, gut 35.2±5.0%, Sommersemester: sehr gut 83.9±7.5%, gut 16.1±7.5%)
Zusammenfassung: Zusammenfassend hat sich gezeigt, dass sich das Mentorenprogramm positiv auf die Entwicklung, Ausbildung und Zufriedenheit der Studienanfänger in der Bonner Vorklinik auswirkt.
Introduction: To better prepare young medical students in a thorough and competent manner for the ever increasing clinical, scientific, as well as psychosocial requirements, universities should enable a close, personal transfer of experience and knowledge. Structured mentoring programs are a promising approach to incorporate clinical subjects earlier into the preclinical training. Such a mentoring program facilitates the prioritization of concepts from a broad, theory-heavy syllabus.
Here we report the experiences and results of the preclinical mentoring program of Bonn University, which was introduced in the winter semester of 2012/2013.
Project desciption: The program is characterized by the concept of peer-to-peer teaching during the preclinical semesters of medical school. Regular, voluntary course meetings with different clinical case examples provide students the opportunity to apply knowledge acquired from the basic science curricula; furthermore, a personal contact for advice and support is ensured. Thus, an informal exchange of experiences is made possible, which provides to the students motivational and learning aids, in particular for the oral examination at the end of the premedical semesters as well as for other examinations during medical school.
Results: Over the course of the preceding three years the number of participants and the interest in the program grew steadily. The analysis of collected evaluations confirms very good communication between mentors and students (>80%), as well as consistently good to very good quality and usefulness in terms of the mentors’ subject-specific and other advice. The overall final evaluation of the mentoring program was always good to very good (winter semester: very good 64.8±5.0%, good 35.2±5.0%, summer semester: very good 83.9±7.5%, good 16.1±7.5%)
Summary: In summary, it has been shown that the mentoring program had a positive impact on the development, education and satisfaction of students beginning their preclinical semesters at Bonn University.
Günther, Andreas ; Krauss, Ekaterina ; Tello, Silke ; Wagner, Jasmin ; Paul, Bettina ; Kuhn, Stefan ; Maurer, Olga ; Heinemann, Sabine ; Costabel, Ulrich ; Nieto Barbero, María Asunción ; Müller, Veronika ; Bonniaud, Philippe ; Vancheri, Carlo ; Wells, Athol ; Vasakova, Martina ; Pesci, Alberto ; Sofia, Matteo ; Klepetko, Walter ; Seeger, Werner ; Drakopanagiotakis, Fotios ; Crestani, Bruno
Background: Since 2009, IPF patients across Europe are recruited into the eurIPFreg, providing epidemiological data and biomaterials for translational research.
Methods: The registry data are based on patient and physician baseline and follow-up questionnaires, comprising 1700 parameters. The mid- to long-term objectives of the registry are to provide clues for a better understanding of IPF phenotype sub-clusters, triggering factors and aggravating conditions, regional and environmental characteristics, and of disease behavior and management.
Results: This paper describes baseline data of 525 IPF subjects recruited from 11/2009 until 10/2016. IPF patients had a mean age of 68.1 years, and seeked medical advice due to insidious dyspnea (90.1%), fatigue (69.2%), and dry coughing (53.2%). A surgical lung biopsy was performed in 32% in 2009, but in only 8% of the cases in 2016, possibly due to increased numbers of cryobiopsy. At the time of inclusion in the eurIPFreg, FVC was 68.4% ± 22.6% of predicted value, DLco ranged at 42.1% ± 17.8% of predicted value (mean value ± SD). Signs of pulmonary hypertension were found in 16.8%. Steroids, immunosuppressants and N-Acetylcysteine declined since 2009, and were replaced by antifibrotics, under which patients showed improved survival (p = 0.001).
Conclusions: Our data provide important insights into baseline characteristics, diagnostic and management changes as well as outcome data in European IPF patients over time.
Trial registration: The eurIPFreg and eurIPFbank are listed in ClinicalTrials.gov(NCT02951416).
Ardakani, Fatemeh Behjati ; Kattler, Kathrin ; Nordström, Karl ; Gasparoni, Nina ; Gasparoni, Gilles ; Fuchs, Sarah ; Sinha, Anupam ; Barann, Matthias ; Ebert, Peter ; Fischer, Jonas ; Hutter, Barbara ; Zipprich, Gideon ; Imbusch, Charles D. ; Felder, Bärbel ; Eils, Jürgen ; Brors, Benedikt ; Lengauer, Thomas ; Manke, Thomas ; Rosenstiel, Philip ; Walter, Jörn ; Schulz, Marcel Holger
Background: Bidirectional promoters (BPs) are prevalent in eukaryotic genomes. However, it is poorly understood how the cell integrates different epigenomic information, such as transcription factor (TF) binding and chromatin marks, to drive gene expression at BPs. Single-cell sequencing technologies are revolutionizing the field of genome biology. Therefore, this study focuses on the integration of single-cell RNA-seq data with bulk ChIP-seq and other epigenetics data, for which single-cell technologies are not yet established, in the context of BPs.
Results: We performed integrative analyses of novel human single-cell RNA-seq (scRNA-seq) data with bulk ChIP-seq and other epigenetics data. scRNA-seq data revealed distinct transcription states of BPs that were previously not recognized. We find associations between these transcription states to distinct patterns in structural gene features, DNA accessibility, histone modification, DNA methylation and TF binding profiles.
Conclusions: Our results suggest that a complex interplay of all of these elements is required to achieve BP-specific transcriptional output in this specialized promoter configuration. Further, our study implies that novel statistical methods can be developed to deconvolute masked subpopulations of cells measured with different bulk epigenomic assays using scRNA-seq data.
Murakami, Naoya ; Ueno, Takao ; Yatsuoka, Wakako ; Okamoto, Hiroyuki ; Tselis, Nikolaos ; Masui, Koji ; Yoshida, Ken ; Takahashi, Kana ; Inaba, Koji ; Okuma, Kae ; Igaki, Hiroshi ; Nakayama, Yuko ; Itami, Jun
Purpose: When squamous cell carcinoma of the buccal mucosa (BSCC) extends surrounding anatomical sites such as gingiva, retromolar triangle, or hard palate, it might be challenging to ensure adequate tumor coverage by sole interstitial brachytherapy due to the complexity of catheter implantation. By combining interstitial catheters with an enoral placed, individually assembled “oral spacer plus embedded catheters” device (hybrid of intracavitary-interstitial brachytherapy), it should be easier to deliver the necessary tumoricidal dose to irregular-shaped tumor volumes (clinical target volume – CTV) with improved conformity. The purpose of this analysis was to compare the dose distribution created by the hybrid of intracavitary-interstitial brachytherapy (HBT) with the dose distribution of an interstitial catheter only-approach, based on the interstitial catheters used for HBT (ISBT-only) by evaluating respective treatment plans (HBT plan vs. ISBT-only plan) for the treatment of early stage BSCC.
Material and methods: A retrospective analysis was performed for patients with localized BSCC treated between April 2013 and October 2017. All patients received sole HBT without additional external beam radiation therapy or planned neck dissection. Dosimetric parameters taken into account for comparison between actual HBT and virtual ISBT-only were CTV D90, CTV V100, CTV V150, CTV V200, mandible D2cc, and mucosal surface D2cc.
Results: Dosimetrically, HBT showed a trend toward better CTV D90 compared to ISBT-only. In addition, HBT demonstrated statistically better CTV V100 coverage compared to ISBT-only. There was no statistically significant difference with respect to CTV V150, CTV V200, and mucosal surface D2cc, while a trend was seen in better mandible D0.1cc between HBT and ISBT-only.
Conclusions: The HBT approach appears to enable improved dose coverage of irregular-shaped enoral tumor volumes compared to ISBT-only for patients with early stage BSCC.
Jia, Guangshuai ; Preussner, Jens ; Chen, Xi ; Günther, Stefan ; Yuan, Xuejun ; Yekelchyk, Michail ; Künne, Carsten Tobias ; Looso, Mario ; Zhou, Yonggang ; Teichmann, Sarah ; Braun, Thomas
Formation and segregation of cell lineages forming the heart have been studied extensively but the underlying gene regulatory networks and epigenetic changes driving cell fate transitions during early cardiogenesis are still only partially understood. Here, we comprehensively characterize mouse cardiac progenitor cells (CPCs) marked by Nkx2-5 and Isl1 expression from E7.5 to E9.5 using single-cell RNA sequencing and transposase-accessible chromatin profiling (ATAC-seq). By leveraging on cell-to-cell transcriptome and chromatin accessibility heterogeneity, we identify different previously unknown cardiac subpopulations. Reconstruction of developmental trajectories reveal that multipotent Isl1+ CPC pass through an attractor state before separating into different developmental branches, whereas extended expression of Nkx2-5 commits CPC to an unidirectional cardiomyocyte fate. Furthermore, we show that CPC fate transitions are associated with distinct open chromatin states critically depending on Isl1 and Nkx2-5. Our data provide a model of transcriptional and epigenetic regulations during cardiac progenitor cell fate decisions at single-cell resolution.
Zschiebsch, Katja ; Fischer, Caroline ; Wilken-Schmitz, Annett ; Geisslinger, Gerd ; Channon, Keith ; Watschinger, Katrin ; Tegeder, Irmgard
GTP cyclohydrolase (GCH1) governs de novo synthesis of the enzyme cofactor, tetrahydrobiopterin (BH4), which is essential for biogenic amine production, bioactive lipid metabolism and redox coupling of nitric oxide synthases. Overproduction of BH4 via upregulation of GCH1 in sensory neurons is associated with nociceptive hypersensitivity in rodents, and neuron‐specific GCH1 deletion normalizes nociception. The translational relevance is revealed by protective polymorphisms of GCH1 in humans, which are associated with a reduced chronic pain. Because myeloid cells constitute a major non‐neuronal source of BH4 that may contribute to BH4‐dependent phenotypes, we studied here the contribution of myeloid‐derived BH4 to pain and itch in lysozyme M Cre‐mediated GCH1 knockout (LysM‐GCH1−/−) and overexpressing mice (LysM‐GCH1‐HA). Unexpectedly, knockout or overexpression in myeloid cells had no effect on nociceptive behaviour, but LysM‐driven GCH1 knockout reduced, and its overexpression increased the scratching response in Compound 48/80 and hydroxychloroquine‐evoked itch models, which involve histamine and non‐histamine dependent signalling pathways. Mechanistically, GCH1 overexpression increased BH4, nitric oxide and hydrogen peroxide, and these changes were associated with increased release of histamine and serotonin and degranulation of mast cells. LysM‐driven GCH1 knockout had opposite effects, and pharmacologic inhibition of GCH1 provided even stronger itch suppression. Inversely, intradermal BH4 provoked scratching behaviour in vivo and BH4 evoked an influx of calcium in sensory neurons. Together, these loss‐ and gain‐of‐function experiments suggest that itch in mice is contributed by BH4 release plus BH4‐driven mediator release from myeloid immune cells, which leads to activation of itch‐responsive sensory neurons.
Ohlendorf, Daniela Maren ; Marx, Jennifer ; Clasen, Kathrin ; Wanke, Eileen M. ; Kopp, Stefan ; Groneberg, Jan David Alexander ; Uibel, Stefanie
Background: Effects of playing high stringed bow instruments on the upper body posture have not been analysed so far. The instrument-specific seating position when playing in an orchestra is compared to the habitual seating position.
Methods: Three dimensional back scans were performed in 13 professional violinists and viola players of a radio orchestra (8 f / 5 m). Trunk position in their habitual seating position and in the instrument- specific seating position imitating playing was compared. Statistical differences were calculated using Wilcoxon Matched Pairs Test with Bonferroni Holm correction.
Results: Significant differences were found between the seated position with instrument and without (p < 0.001, 0.03, 0.02 or 0.01) in the spine (trunk length, sagittal trunk decline, lumbar bending angle, maximal rotation, standard deviation rotation, lumbar lordosis), the shoulder (scapula distance, scapula rotation, scapula angle right) and pelvis distance.
Conclusions: Playing an instrument changes the static seating position by increased rotation of the spine and specific shoulder adaptations holding the instrument (left arm) and the bow (right arm), with minor effects on the pelvis. This forced position may result in chronic health effects. The method used in this study is an approach to better understand the involved muscular structures and possible resulting health damages.
Mölleken, Christian ; Ahrens, Maike ; Schlosser, Anders ; Dietz, Julia ; Eisenacher, Martin ; Meyer, Helmut E. ; Schmiegel, Wolff ; Holmskov, Uffe ; Sarrazin, Christoph ; Sørensen, Grith Lykke ; Sitek, Barbara ; Bracht, Thilo
Background/Aims: An estimated 80 million people worldwide are infected with viremic hepatitis C virus (HCV). Even after eradication of HCV with direct acting antivirals (DAAs), hepatic fibrosis remains a risk factor for hepatocarcinogenesis. Recently, we confirmed the applicability of microfibrillar-associated protein 4 (MFAP4) as a serum biomarker for the assessment of hepatic fibrosis. The aim of the present study was to assess the usefulness of MFAP4 as a biomarker of liver fibrosis after HCV eliminating therapy with DAAs.
Methods: MFAP4 was measured using an immunoassay in 50 hepatitis C patients at baseline (BL), the end-of-therapy (EoT), and the 12-week follow-up visit (FU). Changes in MFAP4 from BL to FU and their association with laboratory parameters including alanine aminotransferase (ALT), aspartate aminotransferase (AST), platelets, the AST to platelet ratio index (APRI), fibrosis-4 score (FIB-4), and albumin were analyzed.
Results: MFAP4 serum levels were representative of the severity of hepatic fibrosis at BL and correlated well with laboratory parameters, especially APRI (Spearman correlation, R²=0.80). Laboratory parameters decreased significantly from BL to EoT. MFAP4 serum levels were found to decrease from BL and EoT to FU with high statistical significance (Wilcoxon p<0.001 for both).
Conclusions: Our findings indicate that viral eradication resulted in reduced MFAP4 serum levels, presumably representing a decrease in hepatic fibrogenesis or fibrosis. Hence, MFAP4 may be a useful tool for risk assessment in hepatitis C patients with advanced fibrosis after eradication of the virus.
Kische, Hanna ; Hoyer, Jürgen ; Pieper, Lars ; Venz, John ; Klotsche, Jens ; März, Winfried ; Koch-Gromus, Uwe ; Pittrow, David ; Lehnert, Hendrik ; Silber, Sigmund ; Stalla, Günter K. ; Zeiher, Andreas M. ; Wittchen, Hans-Ulrich ; Haring, Robin
Background: Previous experimental research on testosterone (T) and psychological traits is inconclusive. Thus, we performed the first large-scale observational study of the association between T and dispositional optimism / pessimism.
Methods: We used prospective data from 6,493 primary-care patients (3,840 women) of the DETECT study (Diabetes Cardiovascular Risk-Evaluation: Targets and Essential Data for Commitment of Treatment), including repeated immunoassay-based measurement of serum T and optimism / pessimism assessed by the revised Life-Orientation Test (LOT-R). Cross-sectional and longitudinal associations of baseline T and one-year change in T with optimism and pessimism were investigated using age- and multivariable-adjusted regression models.
Results: Cross-sectional analyses showed no association of T with optimism or pessimism in both sexes. Longitudinal analyses also showed no association of baseline T with optimism or pessimism at four-year follow-up. Multivariable analyses of total LOT-R score yielded similarly non-significant results (β-coefficient per unit change in T for men: -0.01 (95% CI: -0.24–0.22), women: 0.08 (-0.03–0.20)). Furthermore, change in T was not related to optimism or pessimism at four-year follow-up.
Conclusions: The present observational study of a large-scale prospective sample showed no association of T with optimism or pessimism. Integrating further experimental and interventional evidence from alternative methodological approaches would strengthen this conclusion and establish stronger evidence about the potential hormonal basis of psychological traits.
Kwankamol Limsopatham ; Hall, Martin J. R. ; Zehner, Richard ; Zajac, Barbara Karolina ; Verhoff, Marcel A. ; Narin Sontigun ; Kom Sukontason ; Kabkaew L. Sukontason ; Amendt, Jens
The bluebottle blow fly Calliphora vicina is a common species distributed throughout Europe that can play an important role as forensic evidence in crime investigations. Developmental rates of C. vicina from distinct populations from Germany and England were compared under different temperature regimes to explore the use of growth data from different geographical regions for local case work. Wing morphometrics and molecular analysis between these populations were also studied as indicators for biological differences. One colony each of German and English C. vicina were cultured at the Institute of Legal Medicine in Frankfurt, Germany. Three different temperature regimes were applied, two constant (16°C & 25°C) and one variable (17–26°C, room temperature = RT). At seven time points (600, 850, 1200, 1450, 1800, 2050, and 2400 accumulated degree hours), larval lengths were measured; additionally, the durations of the post feeding stage and intrapuparial metamorphosis were recorded. For the morphometric and molecular study, 184 females and 133 males from each C. vicina population (Germany n = 3, England n = 4) were sampled. Right wings were measured based on 19 landmarks and analyzed using canonical variates analysis and discriminant function analysis. DNA was isolated from three legs per specimen (n = 61) using 5% chelex. A 784 bp long fragment of the mitochondrial cytochrome b gene was sequenced; sequences were aligned and phylogenetically analyzed. Similar larval growth rates of C. vicina were found from different geographic populations at different temperatures during the major part of development. Nevertheless, because minor differences were found a wider range of temperatures and sampling more time points should be analyzed to obtain more information relevant for forensic case work. Wing shape variation showed a difference between the German and English populations (P<0.0001). However, separation between the seven German and English populations at the smaller geographic scale remained ambiguous. Molecular phylogenetic analysis by maximum likelihood method could not unambiguously separate the different geographic populations at a national (Germany vs England) or local level.
Rooijen, Mathilde van ; Jairam, An ; Tollens, Tim ; Jørgensen, Lars Nannestad ; Vries Reilingh, Tammo S. de ; Piessen, Guillaume ; Köckerling, Ferdinand ; Miserez, Marc ; Windsor, Alastair C. J. ; Berrevoet, Frederik ; Fortelny, René H. ; Dousset, Bertrand ; Woeste, Guido ; Westreenen, Henderik Leendert van ; Gossetti, Francesco ; Lange, Johan F. ; Tetteroo, Geert W. M. ; Koch, Andreas ; Kroese, Leonard F. ; Jeekel, Johannes
Background: Incisional heia is a frequent complication of midline laparotomy. The use of mesh in hernia repair has been reported to lead to fewer recurrences compared to primary repair. However, in Ventral Hernia Working Group (VHWG) Grade 3 hernia patients, whose hernia is potentially contaminated, synthetic mesh is prone to infection. There is a strong preference for resorbable biological mesh in contaminated fields, since it is more able to resist infection, and because it is fully resorbed, the chance of a foreign body reaction is reduced. However, when not crosslinked, biological resorbable mesh products tend to degrade too quickly to facilitate native cellular ingrowth. Phasix™ Mesh is a biosynthetic mesh with both the biocompatibility and resorbability of a biological mesh and the mechanical strength of a synthetic mesh. This multi-center single-arm study aims to collect data on safety and performance of Phasix™ Mesh in Grade 3 hernia patients.
Methods: A total of 85 VHWG Grade 3 hernia patients will be treated with Phasix™ Mesh in 15 sites across Europe. The primary outcome is Surgical Site Occurrence (SSO) including hematoma, seroma, infection, dehiscence and fistula formation (requiring intervention) through 3 months. Secondary outcomes include recurrence, infection and quality of life related outcomes after 24 months. Follow-up visits will be at drain removal (if drains were not placed, then on discharge or staple removal instead) and in the 1st, 3rd, 6th, 12th, 18th and 24th month after surgery.
Conclusion: Based on evidence from this clinical study Depending on the results this clinical study will yield, Phasix™ Mesh may become a preferred treatment option in VHWG Grade 3 patients.
Trial registration: The trial was registered on March 25, 2016 on clinicaltrials.gov: NCT02720042.
Operating in a reverberating regime enables rapid tuning of network states to task requirements
(2018)
Wilting, Jens ; Dehning, Jonas ; Neto, Joao Pinheiro ; Rudelt, Lucas ; Wibral, Michael ; Zierenberg, Johannes ; Priesemann, Viola
Neural circuits are able to perform computations under very diverse conditions and requirements. The required computations impose clear constraints on their fine-tuning: a rapid and maximally informative response to stimuli in general requires decorrelated baseline neural activity. Such network dynamics is known as asynchronous-irregular. In contrast, spatio-temporal integration of information requires maintenance and transfer of stimulus information over extended time periods. This can be realized at criticality, a phase transition where correlations, sensitivity and integration time diverge. Being able to flexibly switch, or even combine the above properties in a task-dependent manner would present a clear functional advantage. We propose that cortex operates in a "reverberating regime" because it is particularly favorable for ready adaptation of computational properties to context and task. This reverberating regime enables cortical networks to interpolate between the asynchronous-irregular and the critical state by small changes in effective synaptic strength or excitation-inhibition ratio. These changes directly adapt computational properties, including sensitivity, amplification, integration time and correlation length within the local network. We review recent converging evidence that cortex in vivo operates in the reverberating regime, and that various cortical areas have adapted their integration times to processing requirements. In addition, we propose that neuromodulation enables a fine-tuning of the network, so that local circuits can either decorrelate or integrate, and quench or maintain their input depending on task. We argue that this task-dependent tuning, which we call "dynamic adaptive computation," presents a central organization principle of cortical networks and discuss first experimental evidence.
Lenhard, Thorsten ; Ott, Daniela ; Jakob, Nurith Juliane ; Martinez Torres, Francisco Javier ; Grond-Ginsbach, Caspar ; Meyding-Lamadé, Uta
Background: Tick-borne encephalitis (TBE) is endemic in southern and eastern districts of Germany. Approximately 10–14% of the infected individuals suffer from long-term disability and in 1.5–3.6% the course is fatal. Two well-tolerated vaccines are available, which provide high protection and which have been confirmed in several field studies. Here we investigate clinical course, long-term outcome and cerebrospinal fluid (CSF) characteristics of TBE cases with a prior history of any vaccination as well as real vaccination breakthrough (VBT).
Methods: A case series of 11 patients with a prior history of vaccination, part of a recently published lager cohort of 111 TBE cases. Evaluation included clinical data, degree of disability (modified RANKIN scale, mRS) and analysis of CSF and serum samples. Furthermore, metadata for extended analysis on clinical outcome of TBE with VBT were analysed.
Results: One patient had a clear VBT and ten of them had irregular vaccinations schedules (IVS). Infection severity did not differ in patients with IVS as compared to a non-vaccinated control cohort (median mRS: both 3.0) but these patients showed a stronger cellular immune response as measured by CSF pleocytosis (IVS, 205 cells/μL versus non-vaccinated control, 114 cell/μL, P < 0.05) and by differential pattern of CSF (intrathecal) immunoglobulin synthesis. However, shift analysis of VBT metadata using linear-by-linear association revealed a more serious course of TBE in patients with VBT than in a non-vaccinated control cohort (χ2 = 9.95, P = 0.002). Furthermore, ordinal logistic regression analysis showed that VBT patients had an age-corrected, 2.65 fold (CI: 1.110–6.328; χ2 = 4.813; p = 0.028) significant higher risk to suffer from moderate or severe infections, respectively.
Conclusion: A history of IVS surprisingly seems to have no impact on the clinical course of TBE but may leave marks in the specific brain immune response. VBT patients, however, carry an age-independent, significant risk to experience a severe infection.
Klöppel, Stefan ; Yang, Shan ; Kellner, Elias ; Reisert, Marco ; Heimbach, Bernhard ; Urbach, Horst ; Linn, Jennifer ; Weidauer, Stefan ; Andres, Tamara ; Bröse, Maximilian ; Lahr, Jacob ; Lützen, Niklas ; Meyer, Philipp Tobias ; Peter, Jessica ; Abdulkadir, Ahmed ; Hellwig, Sabine ; Egger, Karl
The identification of pathological atrophy in MRI scans requires specialized training, which is scarce outside dedicated centers. We sought to investigate the clinical usefulness of computer-generated representations of local grey matter (GM) loss or increased volume of cerebral fluids (CSF) as normalized deviations (z-scores) from healthy aging to either aid human visual readings or directly detect pathological atrophy.
Two experienced neuroradiologists rated atrophy in 30 patients with Alzheimer's disease (AD), 30 patients with frontotemporal dementia (FTD), 30 with dementia due to Lewy-body disease (LBD) and 30 healthy controls (HC) on a three-point scale in 10 anatomical regions as reference gold standard. Seven raters, varying in their experience with MRI diagnostics rated all cases on the same scale once with and once without computer-generated volume deviation maps that were overlaid on anatomical slices. In addition, we investigated the predictive value of the computer generated deviation maps on their own for the detection of atrophy as identified by the gold standard raters.
Inter and intra-rater agreements of the two gold standard raters were substantial (Cohen's kappa κ > 0.62). The intra-rater agreement of the other raters ranged from fair (κ = 0.37) to substantial (κ = 0.72) and improved on average by 0.13 (0.57 < κ < 0.87) when volume deviation maps were displayed. The seven other raters showed good agreement with the gold standard in regions including the hippocampus but agreement was substantially lower in e.g. the parietal cortex and did not improve with the display of atrophy scores. Rating speed increased over the course of the study and irrespective of the presentation of voxel-wise deviations.
Automatically detected large deviations of local volume were consistently associated with gold standard atrophy reading as shown by an area under the receiver operator characteristic of up to 0.95 for the hippocampus region. When applying these test characteristics to prevalences typically found in a memory clinic, we observed a positive or negative predictive value close to or above 0.9 in the hippocampus for almost all of the expected cases. The volume deviation maps derived from CSF volume increase were generally better in detecting atrophy.
Our study demonstrates an agreement of visual ratings among non-experts not further increased by displaying, region-specific deviations of volume. The high predictive value of computer generated local deviations independent from human interaction and the consistent advantages of CSF-over GM-based estimations should be considered in the development of diagnostic tools and indicate clinical utility well beyond aiding visual assessments.
Parey, Kristian Kurt ; Brandt, Ulrich ; Xie, Hao ; Mills, Deryck J. ; Siegmund, Karin ; Vonck, Janet ; Kühlbrandt, Werner ; Zickermann, Volker
Mitochondrial complex I has a key role in cellular energy metabolism, generating a major portion of the proton motive force that drives aerobic ATP synthesis. The hydrophilic arm of the L-shaped ~1 MDa membrane protein complex transfers electrons from NADH to ubiquinone, providing the energy to drive proton pumping at distant sites in the membrane arm. The critical steps of energy conversion are associated with the redox chemistry of ubiquinone. We report the cryo-EM structure of complete mitochondrial complex I from the aerobic yeast Yarrowia lipolytica both in the deactive form and after capturing the enzyme during steady-state activity. The site of ubiquinone binding observed during turnover supports a two-state stabilization change mechanism for complex I.