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Sein Schmidt

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Università Di Messina

Adriel M . Pastrana

Gilson Tanaka Shinzato

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University of Pisa

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neysa regattieri

Larissa Cristina De Melo Bruno

Antje Vogelgesang

Alexa Kupferschmitt

Universitätsklinikum Regensburg

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Papers by Sein Schmidt

Fatigue and cognitive impairment after COVID-19: A prospective multicentre study

eClinicalMedicine

Background Reliable estimates of frequency, severity and associated factors of both fatigue and c... more Background Reliable estimates of frequency, severity and associated factors of both fatigue and cognitive impairment after COVID-19 are needed. Also, it is not clear whether the two are distinct sequelae of COVID-19 or part of the same syndrome. Methods In this prospective multicentre study, frequency of post-COVID fatigue and cognitive impairment were assessed in n = 969 patients (535 [55%] female) ≥6 months after SARS-CoV-2 infection with the FACIT-Fatigue scale (cut-off ≤30) and Montreal Cognitive Assessment (≤25 mild, ≤17 moderate impairment) between November 15, 2020 and

Bandwidth-Specific Functional Connectivity of Physiological Low Frequency Oscillations in fMRI

With over forty publications on resting state connectivity in functional magnetic resonance imagi... more With over forty publications on resting state connectivity in functional magnetic resonance imaging (fMRI) and over fifty years of invasive research in animals, the origin of various low frequency oscillatory states remains unresolved. Here the question will be answered: Is it possible to differentiate functional connectivity into two bandwidths, i.e. at very low and low frequencies? If it is possible to differentiate two bandwidths in fMRI resting state connectivity, then a connection to investigations from other modalities with well-defined physiological and pathological relevance can be established. A review of previous literature suggests that low frequency oscillations dominate in "very low frequencies" rather than in "low frequencies", i.e. 0.04 Hz versus 0.08 Hz. Further, it is plausible that both bandwidths co-exist independent of each other, have a neural origin, and are independent of cerebral vasomotion as well as cardiac and respiratory cycles. We app...

Image-Guided Brain Navigation in TMS Practice

Reappraisal of the anatomical landmarks of motor and premotor cortical regions for image-guided b... more

Treatment Realities of Headache Disorders in Rural Germany by the Example of the Region of Western Pomerania

Brain Sciences, 2021

This article is an open access article distributed under the terms and conditions of the Creative... more

Impact of dexamethasone on SARS-CoV-2 concentration kinetics and antibody response in hospitalized COVID-19 patients: results from a prospective observational study

Clinical Microbiology and Infection, 2021

Since January 2020 Elsevier has created a COVID-19 resource centre with free information in Engli... more Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre -including this research content -immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

Simvastatin add-on to escitalopram in patients with comorbid obesity and major depression (SIMCODE): study protocol of a multicentre, randomised, double-blind, placebo-controlled trial

BMJ Open, 2020

IntroductionMajor depressive disorder (MDD) and obesity are both common disorders associated with... more IntroductionMajor depressive disorder (MDD) and obesity are both common disorders associated with significant burden of disease worldwide. Importantly, MDD and obesity often co-occur, with each disorder increasing the risk for developing the other by about 50%–60%. Statins are among the most prescribed medications with well-established safety and efficacy. Statins are recommended in primary prevention of cardiovascular disease, which has been linked to both MDD and obesity. Moreover, statins are promising candidates to treat MDD because a meta-analysis of pilot randomised controlled trials has found antidepressive effects of statins as adjunct therapy to antidepressants. However, no study so far has tested the antidepressive potential of statins in patients with MDD and comorbid obesity. Importantly, this is a difficult-to-treat population that often exhibits a chronic course of MDD and is more likely to be treatment resistant. Thus, in this confirmatory randomised controlled trial,...

Delayed Antibody and T-Cell Response to BNT162b2 Vaccination in the Elderly, Germany

Emerging Infectious Diseases, 2021

T he severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has led to an urgent n... more T he severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has led to an urgent need for vaccines, particularly among persons at high risk for severe disease and death, such as the elderly (1). Effi cacy against severe coronavirus disease (COV-ID-19) of mRNA vaccine BNT162b2 (Pfi zer-BioNTech, https://www.pfi zer.com) is reported to be >90% starting 7 days after the second vaccination; robust antibody and T-cell response has been demonstrated consistently across age groups (2-4). However, only 4.3% of participants in the BNT162b2 effi cacy trial were >75 years of age (4). Given the elderly generally have weaker immune responses after vaccination, more detailed investigation is necessary (4,5). The Study In a prospective observational cohort study, we investigated SARS-CoV-2-specifi c antibodies, maturation of IgG avidity, and interferon-γ (IFN-γ) release of SARS-CoV-2-specifi c T cells in 2 cohorts of young and elderly BNT162b2-vaccinated persons (Table). Participants were recruited from 2 studies conducted at Charité-Universitätsmedizin Berlin, both conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (https://www.ema.europa. eu/en/documents/scientific-guideline/ich-e-6-r2guideline-good-clinical-practice-step-5_en.pdf) and approved by the local ethics committee (EA4/244/20 and EA4/245/20) The fi rst cohort consisted of 123 healthcare workers; median age was 34 (interquartile range [IQR] 20-64) years. The second cohort consisted of 71 elderly residents of an assisted living facility; median age was 81 (IQR 70-96) years. Blood samples were taken before the fi rst vaccination (week 0), just before the second vaccination (week 3), and 4 weeks after the second vaccination (week 7). To discriminate between vaccine-induced antibody response and convalescent SARS-CoV-2 infection, we used the SeraSpot Anti-SARS-CoV-2 IgG microarray-based immunoassay including nucleocapsid and spike as antigens (Seramun Diagnostica GmbH, https://www.seramun.com) (Appendix,

Cross-talk between the airway epithelium and activated immune cells defines severity in COVID-19

ABSTRACTThe clinical course of COVID-19 is highly variable, however, underlying host factors and ... more ABSTRACTThe clinical course of COVID-19 is highly variable, however, underlying host factors and determinants of severe disease are still unknown. Based on single-cell transcriptomes of nasopharyngeal and bronchial samples from clinically well-characterized patients presenting with moderate and critical severities, we reveal the different types and states of airway epithelial cells that are vulnerable for SARS-CoV-2 infection. In COVID-19 patients, we observed a two- to threefold increase of cells expressing the SARS-CoV-2 entry receptor ACE2 within the airway epithelial cell compartment. ACE2 is upregulated in epithelial cells through Interferon signals by immune cells suggesting that the viral defense system may increase the number of potentially susceptible cells in the respiratory epithelium. Infected epithelial cells recruit and activate immune cells by chemokine signaling. Recruited T lymphocytes and inflammatory macrophages were hyperactivated and showed a strong interaction ...

Safety, reactogenicity, and immunogenicity of homologous and heterologous prime-boost immunisation with ChAdOx1-nCoV19 and BNT162b2: a prospective cohort study

Objectiveto assess reactogenicity and immunogenicity of heterologous prime-boost immunisations of... more Objectiveto assess reactogenicity and immunogenicity of heterologous prime-boost immunisations of ChAdOx1-nCoV19 (Vaxzevria, ChAdOx) followed by BNT162b2 (Comirnaty, BNT) compared to homologous BNT/BNT immunisation.Designprospective, observational cohort study.Settingunicenter study in a cohort of health care workers at a tertiary care center in Berlin, Germany.Participants340 health care workers immunised between 27 December 2020 and 21 May 2021 at Charité - Universitätsmedizin Berlin, GermanyMain outcome measuresthe main outcomes were reactogenicity assessed on days one, three, five and seven post prime and boost vaccination, and immunogenicity measured by serum SARS-CoV-2 full spike-, spike S1-, and spike RBD-IgG, virus neutralisation capacity, anti-S1-IgG avidity, and T cell reactivity measured by Interferon gamma release assay at 3-4 weeks post prime and boost immunisation.ResultsHeterologous ChAdOx/BNT booster vaccination was overall well-tolerated and reactogenicity was large...

Studying the pathophysiology of coronavirus disease 2019 – a protocol for the Berlin prospective COVID-19 patient cohort (Pa-COVID-19)

PurposeSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide causing ... more PurposeSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide causing a global health emergency. Pa-COVID-19 aims to provide comprehensive data on clinical course, pathophysiology, immunology and outcome of COVID-19, in order to identify prognostic biomarkers, clinical scores, and therapeutic targets for improved clinical management and preventive interventions.MethodsPa-COVID-19 is a prospective observational cohort study of patients with confirmed SARS-CoV-2 infection treated at Charité - Universitätsmedizin Berlin. We collect data on epidemiology, demography, medical history, symptoms, clinical course, pathogen testing and treatment. Systematic, serial blood sampling will allow deep molecular and immunological phenotyping, transcriptomic profiling, and comprehensive biobanking. Longitudinal data and sample collection during hospitalization will be supplemented by long-term follow-up.ResultsOutcome measures include the WHO clinical ordinal scale on day 1...

COVID-19 severity correlates with airway epithelium–immune cell interactions identified by single-cell analysis

Nature Biotechnology, 2020

atients with COVID-19 exhibit a broad spectrum of disease progression, with 81% showing mild, mod... more atients with COVID-19 exhibit a broad spectrum of disease progression, with 81% showing mild, moderate or no symptoms; 14% showing severe symptoms; and 5% experiencing critical disease with high mortality risk 1 . The risk of developing severe or critical disease has been associated with advanced age 1,2 , comorbidities 1,2 , hyperactivation of the immune system 3,4 , sex 1,2 and other factors. However, an understanding of these risk factors at the molecular and cellular levels is in its infancy. In this study, we investigated the immune response in patients with COVID-19 by single-cell RNA sequencing (scRNA-seq) of nasopharyngeal and bronchial samples to identify molecular correlates of disease severity. Two recent studies applied scRNA-seq to bronchioalveolar lavage fluid samples from patients with COVID-19 and provide an extensive characterization of the inflammatory immune phenotype in the lower respiratory tract 5,6 . However, SARS-CoV-2 and other coronaviruses infect and replicate in both COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis

Safety Aspects, Tolerability and Modeling of Retinofugal Alternating Current Stimulation

Frontiers in Neuroscience, 2019

Background: While alternating current stimulation (ACS) is gaining relevance as a tool in researc... more Background: While alternating current stimulation (ACS) is gaining relevance as a tool in research and approaching clinical applications, its mechanisms of action remain unclear. A review by Schutter and colleagues argues for a retinal origin of transcranial ACS' neuromodulatory effects. Interestingly, there is an alternative application form of ACS specifically targeting α-oscillations in the visual cortex via periorbital electrodes (retinofugal alternating current stimulation, rACS). To further compare these two methods and investigate retinal effects of ACS, we first aim to establish the safety and tolerability of rACS. Objective: The goal of our research was to evaluate the safety of rACS via finite-element modeling, theoretical safety limits and subjective report. Methods: 20 healthy subjects were stimulated with rACS as well as photic stimulation and reported adverse events following stimulation. We analyzed stimulation parameters at electrode level as well as distributed metric estimates from an ultra-high spatial resolution magnetic resonance imaging (MRI)-derived finite element human head model and compared them to existing safety limits. Results: Topographical modeling revealed the highest current densities in the anterior visual pathway, particularly retina and optic nerve. Stimulation parameters and finite element modeling estimates of rACS were found to be well below existing safety limits. No serious adverse events occurred. Our findings are in line with existing safety guidelines for retinal and neural damage and establish the tolerability and feasibility of rACS. In comparison to tACS, retinofugal stimulation of the visual cortex provides an anatomically circumscribed model to systematically study the mechanisms of action of ACS.

Disease overarching mechanisms that explain and predict outcome of patients with high cardiovascular risk: rationale and design of the Berlin Long-term Observation of Vascular Events (BeLOVE) study

Background: Cardiovascular disease (CVD) is the leading cause of premature death worldwide. Effec... more Background: Cardiovascular disease (CVD) is the leading cause of premature death worldwide. Effective and individualized treatment requires exact knowledge about both risk factors and risk estimation. Most evidence for risk prediction currently comes from population-based studies on first incident cardiovascular events. In contrast, little is known about the relevance of risk factors for the outcome of patients with established CVD or those who are at high risk of CVD, including patients with type 2 diabetes. In addition, most studies focus on individual diseases, whereas less is known about disease overarching risk factors and cross-over risk. Aim: The aim of BeLOVE is to improve short- and long-term prediction and mechanistic understanding of cardiovascular disease progression and outcomes in very high-risk patients, both in the acute as well as in the chronic phase, in order to provide the basis for improved, individualized management. Study design: BeLOVE is an observational pro...

Motor Task-Dependent Dissociated Effects of Transcranial Random Noise Stimulation in a Finger-Tapping Task Versus a Go/No-Go Task on Corticospinal Excitability and Task Performance

Frontiers in Neuroscience, 2019

Task-Dependent Dissociated Effects of tRNS inhibitory control was enhanced as shown by slowed rea... more Task-Dependent Dissociated Effects of tRNS inhibitory control was enhanced as shown by slowed reaction times and enhanced task accuracy during and after stimulation. We provide evidence that tRNS-induced neuromodulatory effects are task-dependent and that resulting enhancements are specific to the underlying task-dependent brain state. While mechanisms underlying this effect require further investigation, these findings highlight the potential of tRNS in enhancing task-dependent brain states to modulate human behavior.

Rebound or Entrainment? The Influence of Alternating Current Stimulation on Individual Alpha

Frontiers in Human Neuroscience, 2019

Alternating current stimulation (ACS) is an established means to manipulate intrinsic cortical os... more Alternating current stimulation (ACS) is an established means to manipulate intrinsic cortical oscillations. While working towards clinical impact, ACS mechanisms of action remain unclear. For ACS's well-documented influence on occipital alpha, hypotheses include neuronal entrainment as well as rebound phenomena. As a retinal origin is also discussed, we employed a novel form of ACS with the advantage that it specifically targets occipital alpha-oscillations via retinofugal pathways retinofugal ACS (rACS). We aimed to confirm alpha-enhancement outlasting the duration of stimulation with 10 Hz rACS. To distinguish entrainment from rebound effects, we investigated the correlation between alpha peak frequency change and alpha-enhancement strength. We quantified the alpha band power before and after 10 Hz rACS in 15 healthy subjects. Alpha power enhancement and alpha peak frequency change were assessed over the occipital electrodes and compared to sham stimulation. RACS significantly enhanced occipital alpha power in comparison to sham stimulation (p < 0.05). Alpha peak frequency changed by a mean 0.02 Hz (± 0.04). A greater change in alpha peak frequency did not correlate with greater effects on alpha power. Our findings show an alpha-enhancement consistent with studies conducted for transcranial ACS (tACS) and contribute evidence for a retinal involvement in tACS effects on occipital alpha. Furthermore, the lack of correlation between alpha peak frequency change and alphaenhancement strength provides an argument against entrainment effects and in favor of a rebound phenomenon.

Delirium is associated with frequency band specific dysconnectivity in intrinsic connectivity networks: preliminary evidence from a large retrospective pilot case-control study

Pilot and Feasibility Studies, 2019

Background: Pathophysiological concepts in delirium are not sufficient to define objective biomar... more Background: Pathophysiological concepts in delirium are not sufficient to define objective biomarkers suited to improve clinical approaches. Advances in neuroimaging have revalued electroencephalography (EEG) as a tool to assess oscillatory network activity in neuropsychiatric disease. Yet, research in the field is limited to small populations and largely confined to postoperative delirium, which impedes generalizability of findings and planning of prospective studies in other populations. This study aimed to assess effect sizes of connectivity measures in a large mixed population to demonstrate that there are measurable EEG differences between delirium and control patients. Methods: This retrospective pilot study investigated EEG measures as biomarkers in delirium using a case-control design including patients diagnosed with delirium (DSM-5 criteria) and age-/gender-matched controls drawn from a database of 9980 patients (n = 129 and 414, respectively). Assessors were not blinded for groups. Power spectra and connectivity estimates, using the weighted phase log index, of continuous EEG data were compared between conditions. Alterations of information flow through nodes of intrinsic connectivity networks (ICN; default mode, salience, and executive control network) were evaluated in source space using betweenness centrality. This was done frequency specific and network nodes were defined by the multimodal human cerebral cortex parcellation based on human connectome project data. Results: Delirium and control patients exhibited distinct EEG power, connectivity, and network characteristics (F (72,540) = 70.3, p < .001; F (493,1079) = 2.69, p < .001; and F (718,2159) = 1.14, p = .007, respectively). Connectivity analyses revealed global alpha and regional beta band disconnectivity that was accompanied by theta band hyperconnectivity in delirious patients. Source and network analyses yielded that these changes are not specific to single intrinsic connectivity networks but affect multiple nodes of networks engaged in level of consciousness, attention, working memory, executive control, and salience detection. Effect sizes were medium to strong in this mixed population of delirious patients.

Force Increase in a Repetitive Motor Task Inducing Motor Fatigue

Journal of motor behavior, Jan 10, 2018

To evaluate task induced motor fatigue in a well-established finger tapping task, we analyzed tap... more To evaluate task induced motor fatigue in a well-established finger tapping task, we analyzed tapping parameters and included the time course of measures of force. We hypothesized that a decline in tapping force would reflect task induced motor fatigue, defined by a lengthening of inter-tap intervals (ITI). A secondary aim was to investigate the reliability of tapping data acquisition with the force sensor. Results show that, as expected, tapping speed decreased linearly over time, due to both an increase of ITI and tap duration. In contrast, tapping force increased non-linearly over time and was uncorrelated to changes in tapping speed. Force data could serve as a measure to characterize task induced motor fatigue. Force sensors can assess a decline in tapping speed as well as an independent increase of tapping force. We argue that the increase of force reflects central compensation, i.e. perception of fatigue, due to an increase in task effort and difficulty.

Diagnostic Performance and Utility of Quantitative EEG Analyses in Delirium: Confirmatory Results From a Large Retrospective Case-Control Study

Clinical EEG and neuroscience, 2018

The lack of objective disease markers is a major cause of misdiagnosis and nonstandardized approa... more The lack of objective disease markers is a major cause of misdiagnosis and nonstandardized approaches in delirium. Recent studies conducted in well-selected patients and confined study environments suggest that quantitative electroencephalography (qEEG) can provide such markers. We hypothesize that qEEG helps remedy diagnostic uncertainty not only in well-defined study cohorts but also in a heterogeneous hospital population. In this retrospective case-control study, EEG power spectra of delirious patients and age-/gender-matched controls (n = 31 and n = 345, respectively) were fitted in a linear model to test their performance as binary classifiers. We subsequently evaluated the diagnostic performance of the best classifiers in control samples with normal EEGs (n = 534) and real-world samples including pathologic findings (n = 4294). Test reliability was estimated through split-half analyses. We found that the combination of spectral power at F3-P4 at 2 Hz (area under the curve [AUC...

Mobile electronic versus paper case report forms in clinical trials: a randomized controlled trial

BMC medical research methodology, 2017

Regulations, study design complexity and amounts of collected and shared data in clinical trials ... more Regulations, study design complexity and amounts of collected and shared data in clinical trials render efficient data handling procedures inevitable. Recent research suggests that electronic data capture can be key in this context but evidence is insufficient. This randomized controlled parallel group study tested the hypothesis that time efficiency is superior when electronic (eCRF) instead of paper case report forms (pCRF) are used for data collection. We additionally investigated predictors of time saving effects and data integrity. This study was conducted on top of a clinical weight loss trial performed at a clinical research facility over six months. All study nurses and patients participating in the clinical trial were eligible to participate and randomly allocated to enter cross-sectional data obtained during routine visits either through pCRF or eCRF. A balanced randomization list was generated before enrolment commenced. 90 and 30 records were gathered for the time that 2...

P1066: Movement preparation requires early activation of the dorsal premotor area

Clinical Neurophysiology, 2014

before and after the exercise on day 1 (T0, T1) and after the exercise on day 5 (T2). Basketball ... more before and after the exercise on day 1 (T0, T1) and after the exercise on day 5 (T2). Basketball players attended only to T0 and T1. Results: In FCR of the sedentary group (Fig. 1, amplitude ratios, blue: T0, red: T1, green: T2, bars: standard deviations), there were less short latency afferent inhibition and higher facilitation at T1 (statistically significant at ISI 35 and 50 ms). This effect decreased at T2 despite the increased success rate. Basketball players did not show a facilitation as high as that found in the sedentary group. Conclusion: Short term exercises lead to SMI changes which may function in the early phase of gaining the ability. Continued training provided higher success while the electrophysiological changes was decreasing, possibly by the conversion of the learning process into different mechanisms. Exercising already gained abilities do not produce similar SMI changes.

Fatigue and cognitive impairment after COVID-19: A prospective multicentre study

eClinicalMedicine

Background Reliable estimates of frequency, severity and associated factors of both fatigue and c... more Background Reliable estimates of frequency, severity and associated factors of both fatigue and cognitive impairment after COVID-19 are needed. Also, it is not clear whether the two are distinct sequelae of COVID-19 or part of the same syndrome. Methods In this prospective multicentre study, frequency of post-COVID fatigue and cognitive impairment were assessed in n = 969 patients (535 [55%] female) ≥6 months after SARS-CoV-2 infection with the FACIT-Fatigue scale (cut-off ≤30) and Montreal Cognitive Assessment (≤25 mild, ≤17 moderate impairment) between November 15, 2020 and

Bandwidth-Specific Functional Connectivity of Physiological Low Frequency Oscillations in fMRI

With over forty publications on resting state connectivity in functional magnetic resonance imagi... more With over forty publications on resting state connectivity in functional magnetic resonance imaging (fMRI) and over fifty years of invasive research in animals, the origin of various low frequency oscillatory states remains unresolved. Here the question will be answered: Is it possible to differentiate functional connectivity into two bandwidths, i.e. at very low and low frequencies? If it is possible to differentiate two bandwidths in fMRI resting state connectivity, then a connection to investigations from other modalities with well-defined physiological and pathological relevance can be established. A review of previous literature suggests that low frequency oscillations dominate in "very low frequencies" rather than in "low frequencies", i.e. 0.04 Hz versus 0.08 Hz. Further, it is plausible that both bandwidths co-exist independent of each other, have a neural origin, and are independent of cerebral vasomotion as well as cardiac and respiratory cycles. We app...

Image-Guided Brain Navigation in TMS Practice

Reappraisal of the anatomical landmarks of motor and premotor cortical regions for image-guided b... more

Treatment Realities of Headache Disorders in Rural Germany by the Example of the Region of Western Pomerania

Brain Sciences, 2021

This article is an open access article distributed under the terms and conditions of the Creative... more

Impact of dexamethasone on SARS-CoV-2 concentration kinetics and antibody response in hospitalized COVID-19 patients: results from a prospective observational study

Clinical Microbiology and Infection, 2021

Since January 2020 Elsevier has created a COVID-19 resource centre with free information in Engli... more Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre -including this research content -immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

Simvastatin add-on to escitalopram in patients with comorbid obesity and major depression (SIMCODE): study protocol of a multicentre, randomised, double-blind, placebo-controlled trial

BMJ Open, 2020

IntroductionMajor depressive disorder (MDD) and obesity are both common disorders associated with... more IntroductionMajor depressive disorder (MDD) and obesity are both common disorders associated with significant burden of disease worldwide. Importantly, MDD and obesity often co-occur, with each disorder increasing the risk for developing the other by about 50%–60%. Statins are among the most prescribed medications with well-established safety and efficacy. Statins are recommended in primary prevention of cardiovascular disease, which has been linked to both MDD and obesity. Moreover, statins are promising candidates to treat MDD because a meta-analysis of pilot randomised controlled trials has found antidepressive effects of statins as adjunct therapy to antidepressants. However, no study so far has tested the antidepressive potential of statins in patients with MDD and comorbid obesity. Importantly, this is a difficult-to-treat population that often exhibits a chronic course of MDD and is more likely to be treatment resistant. Thus, in this confirmatory randomised controlled trial,...

Delayed Antibody and T-Cell Response to BNT162b2 Vaccination in the Elderly, Germany

Emerging Infectious Diseases, 2021

T he severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has led to an urgent n... more T he severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has led to an urgent need for vaccines, particularly among persons at high risk for severe disease and death, such as the elderly (1). Effi cacy against severe coronavirus disease (COV-ID-19) of mRNA vaccine BNT162b2 (Pfi zer-BioNTech, https://www.pfi zer.com) is reported to be >90% starting 7 days after the second vaccination; robust antibody and T-cell response has been demonstrated consistently across age groups (2-4). However, only 4.3% of participants in the BNT162b2 effi cacy trial were >75 years of age (4). Given the elderly generally have weaker immune responses after vaccination, more detailed investigation is necessary (4,5). The Study In a prospective observational cohort study, we investigated SARS-CoV-2-specifi c antibodies, maturation of IgG avidity, and interferon-γ (IFN-γ) release of SARS-CoV-2-specifi c T cells in 2 cohorts of young and elderly BNT162b2-vaccinated persons (Table). Participants were recruited from 2 studies conducted at Charité-Universitätsmedizin Berlin, both conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (https://www.ema.europa. eu/en/documents/scientific-guideline/ich-e-6-r2guideline-good-clinical-practice-step-5_en.pdf) and approved by the local ethics committee (EA4/244/20 and EA4/245/20) The fi rst cohort consisted of 123 healthcare workers; median age was 34 (interquartile range [IQR] 20-64) years. The second cohort consisted of 71 elderly residents of an assisted living facility; median age was 81 (IQR 70-96) years. Blood samples were taken before the fi rst vaccination (week 0), just before the second vaccination (week 3), and 4 weeks after the second vaccination (week 7). To discriminate between vaccine-induced antibody response and convalescent SARS-CoV-2 infection, we used the SeraSpot Anti-SARS-CoV-2 IgG microarray-based immunoassay including nucleocapsid and spike as antigens (Seramun Diagnostica GmbH, https://www.seramun.com) (Appendix,

Cross-talk between the airway epithelium and activated immune cells defines severity in COVID-19

ABSTRACTThe clinical course of COVID-19 is highly variable, however, underlying host factors and ... more ABSTRACTThe clinical course of COVID-19 is highly variable, however, underlying host factors and determinants of severe disease are still unknown. Based on single-cell transcriptomes of nasopharyngeal and bronchial samples from clinically well-characterized patients presenting with moderate and critical severities, we reveal the different types and states of airway epithelial cells that are vulnerable for SARS-CoV-2 infection. In COVID-19 patients, we observed a two- to threefold increase of cells expressing the SARS-CoV-2 entry receptor ACE2 within the airway epithelial cell compartment. ACE2 is upregulated in epithelial cells through Interferon signals by immune cells suggesting that the viral defense system may increase the number of potentially susceptible cells in the respiratory epithelium. Infected epithelial cells recruit and activate immune cells by chemokine signaling. Recruited T lymphocytes and inflammatory macrophages were hyperactivated and showed a strong interaction ...

Safety, reactogenicity, and immunogenicity of homologous and heterologous prime-boost immunisation with ChAdOx1-nCoV19 and BNT162b2: a prospective cohort study

Objectiveto assess reactogenicity and immunogenicity of heterologous prime-boost immunisations of... more Objectiveto assess reactogenicity and immunogenicity of heterologous prime-boost immunisations of ChAdOx1-nCoV19 (Vaxzevria, ChAdOx) followed by BNT162b2 (Comirnaty, BNT) compared to homologous BNT/BNT immunisation.Designprospective, observational cohort study.Settingunicenter study in a cohort of health care workers at a tertiary care center in Berlin, Germany.Participants340 health care workers immunised between 27 December 2020 and 21 May 2021 at Charité - Universitätsmedizin Berlin, GermanyMain outcome measuresthe main outcomes were reactogenicity assessed on days one, three, five and seven post prime and boost vaccination, and immunogenicity measured by serum SARS-CoV-2 full spike-, spike S1-, and spike RBD-IgG, virus neutralisation capacity, anti-S1-IgG avidity, and T cell reactivity measured by Interferon gamma release assay at 3-4 weeks post prime and boost immunisation.ResultsHeterologous ChAdOx/BNT booster vaccination was overall well-tolerated and reactogenicity was large...

Studying the pathophysiology of coronavirus disease 2019 – a protocol for the Berlin prospective COVID-19 patient cohort (Pa-COVID-19)

PurposeSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide causing ... more PurposeSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide causing a global health emergency. Pa-COVID-19 aims to provide comprehensive data on clinical course, pathophysiology, immunology and outcome of COVID-19, in order to identify prognostic biomarkers, clinical scores, and therapeutic targets for improved clinical management and preventive interventions.MethodsPa-COVID-19 is a prospective observational cohort study of patients with confirmed SARS-CoV-2 infection treated at Charité - Universitätsmedizin Berlin. We collect data on epidemiology, demography, medical history, symptoms, clinical course, pathogen testing and treatment. Systematic, serial blood sampling will allow deep molecular and immunological phenotyping, transcriptomic profiling, and comprehensive biobanking. Longitudinal data and sample collection during hospitalization will be supplemented by long-term follow-up.ResultsOutcome measures include the WHO clinical ordinal scale on day 1...

COVID-19 severity correlates with airway epithelium–immune cell interactions identified by single-cell analysis

Nature Biotechnology, 2020

atients with COVID-19 exhibit a broad spectrum of disease progression, with 81% showing mild, mod... more atients with COVID-19 exhibit a broad spectrum of disease progression, with 81% showing mild, moderate or no symptoms; 14% showing severe symptoms; and 5% experiencing critical disease with high mortality risk 1 . The risk of developing severe or critical disease has been associated with advanced age 1,2 , comorbidities 1,2 , hyperactivation of the immune system 3,4 , sex 1,2 and other factors. However, an understanding of these risk factors at the molecular and cellular levels is in its infancy. In this study, we investigated the immune response in patients with COVID-19 by single-cell RNA sequencing (scRNA-seq) of nasopharyngeal and bronchial samples to identify molecular correlates of disease severity. Two recent studies applied scRNA-seq to bronchioalveolar lavage fluid samples from patients with COVID-19 and provide an extensive characterization of the inflammatory immune phenotype in the lower respiratory tract 5,6 . However, SARS-CoV-2 and other coronaviruses infect and replicate in both COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis

Safety Aspects, Tolerability and Modeling of Retinofugal Alternating Current Stimulation

Frontiers in Neuroscience, 2019

Background: While alternating current stimulation (ACS) is gaining relevance as a tool in researc... more Background: While alternating current stimulation (ACS) is gaining relevance as a tool in research and approaching clinical applications, its mechanisms of action remain unclear. A review by Schutter and colleagues argues for a retinal origin of transcranial ACS' neuromodulatory effects. Interestingly, there is an alternative application form of ACS specifically targeting α-oscillations in the visual cortex via periorbital electrodes (retinofugal alternating current stimulation, rACS). To further compare these two methods and investigate retinal effects of ACS, we first aim to establish the safety and tolerability of rACS. Objective: The goal of our research was to evaluate the safety of rACS via finite-element modeling, theoretical safety limits and subjective report. Methods: 20 healthy subjects were stimulated with rACS as well as photic stimulation and reported adverse events following stimulation. We analyzed stimulation parameters at electrode level as well as distributed metric estimates from an ultra-high spatial resolution magnetic resonance imaging (MRI)-derived finite element human head model and compared them to existing safety limits. Results: Topographical modeling revealed the highest current densities in the anterior visual pathway, particularly retina and optic nerve. Stimulation parameters and finite element modeling estimates of rACS were found to be well below existing safety limits. No serious adverse events occurred. Our findings are in line with existing safety guidelines for retinal and neural damage and establish the tolerability and feasibility of rACS. In comparison to tACS, retinofugal stimulation of the visual cortex provides an anatomically circumscribed model to systematically study the mechanisms of action of ACS.

Disease overarching mechanisms that explain and predict outcome of patients with high cardiovascular risk: rationale and design of the Berlin Long-term Observation of Vascular Events (BeLOVE) study

Background: Cardiovascular disease (CVD) is the leading cause of premature death worldwide. Effec... more Background: Cardiovascular disease (CVD) is the leading cause of premature death worldwide. Effective and individualized treatment requires exact knowledge about both risk factors and risk estimation. Most evidence for risk prediction currently comes from population-based studies on first incident cardiovascular events. In contrast, little is known about the relevance of risk factors for the outcome of patients with established CVD or those who are at high risk of CVD, including patients with type 2 diabetes. In addition, most studies focus on individual diseases, whereas less is known about disease overarching risk factors and cross-over risk. Aim: The aim of BeLOVE is to improve short- and long-term prediction and mechanistic understanding of cardiovascular disease progression and outcomes in very high-risk patients, both in the acute as well as in the chronic phase, in order to provide the basis for improved, individualized management. Study design: BeLOVE is an observational pro...

Motor Task-Dependent Dissociated Effects of Transcranial Random Noise Stimulation in a Finger-Tapping Task Versus a Go/No-Go Task on Corticospinal Excitability and Task Performance

Frontiers in Neuroscience, 2019

Task-Dependent Dissociated Effects of tRNS inhibitory control was enhanced as shown by slowed rea... more Task-Dependent Dissociated Effects of tRNS inhibitory control was enhanced as shown by slowed reaction times and enhanced task accuracy during and after stimulation. We provide evidence that tRNS-induced neuromodulatory effects are task-dependent and that resulting enhancements are specific to the underlying task-dependent brain state. While mechanisms underlying this effect require further investigation, these findings highlight the potential of tRNS in enhancing task-dependent brain states to modulate human behavior.

Rebound or Entrainment? The Influence of Alternating Current Stimulation on Individual Alpha

Frontiers in Human Neuroscience, 2019

Alternating current stimulation (ACS) is an established means to manipulate intrinsic cortical os... more Alternating current stimulation (ACS) is an established means to manipulate intrinsic cortical oscillations. While working towards clinical impact, ACS mechanisms of action remain unclear. For ACS's well-documented influence on occipital alpha, hypotheses include neuronal entrainment as well as rebound phenomena. As a retinal origin is also discussed, we employed a novel form of ACS with the advantage that it specifically targets occipital alpha-oscillations via retinofugal pathways retinofugal ACS (rACS). We aimed to confirm alpha-enhancement outlasting the duration of stimulation with 10 Hz rACS. To distinguish entrainment from rebound effects, we investigated the correlation between alpha peak frequency change and alpha-enhancement strength. We quantified the alpha band power before and after 10 Hz rACS in 15 healthy subjects. Alpha power enhancement and alpha peak frequency change were assessed over the occipital electrodes and compared to sham stimulation. RACS significantly enhanced occipital alpha power in comparison to sham stimulation (p < 0.05). Alpha peak frequency changed by a mean 0.02 Hz (± 0.04). A greater change in alpha peak frequency did not correlate with greater effects on alpha power. Our findings show an alpha-enhancement consistent with studies conducted for transcranial ACS (tACS) and contribute evidence for a retinal involvement in tACS effects on occipital alpha. Furthermore, the lack of correlation between alpha peak frequency change and alphaenhancement strength provides an argument against entrainment effects and in favor of a rebound phenomenon.

Delirium is associated with frequency band specific dysconnectivity in intrinsic connectivity networks: preliminary evidence from a large retrospective pilot case-control study

Pilot and Feasibility Studies, 2019

Background: Pathophysiological concepts in delirium are not sufficient to define objective biomar... more Background: Pathophysiological concepts in delirium are not sufficient to define objective biomarkers suited to improve clinical approaches. Advances in neuroimaging have revalued electroencephalography (EEG) as a tool to assess oscillatory network activity in neuropsychiatric disease. Yet, research in the field is limited to small populations and largely confined to postoperative delirium, which impedes generalizability of findings and planning of prospective studies in other populations. This study aimed to assess effect sizes of connectivity measures in a large mixed population to demonstrate that there are measurable EEG differences between delirium and control patients. Methods: This retrospective pilot study investigated EEG measures as biomarkers in delirium using a case-control design including patients diagnosed with delirium (DSM-5 criteria) and age-/gender-matched controls drawn from a database of 9980 patients (n = 129 and 414, respectively). Assessors were not blinded for groups. Power spectra and connectivity estimates, using the weighted phase log index, of continuous EEG data were compared between conditions. Alterations of information flow through nodes of intrinsic connectivity networks (ICN; default mode, salience, and executive control network) were evaluated in source space using betweenness centrality. This was done frequency specific and network nodes were defined by the multimodal human cerebral cortex parcellation based on human connectome project data. Results: Delirium and control patients exhibited distinct EEG power, connectivity, and network characteristics (F (72,540) = 70.3, p < .001; F (493,1079) = 2.69, p < .001; and F (718,2159) = 1.14, p = .007, respectively). Connectivity analyses revealed global alpha and regional beta band disconnectivity that was accompanied by theta band hyperconnectivity in delirious patients. Source and network analyses yielded that these changes are not specific to single intrinsic connectivity networks but affect multiple nodes of networks engaged in level of consciousness, attention, working memory, executive control, and salience detection. Effect sizes were medium to strong in this mixed population of delirious patients.

Force Increase in a Repetitive Motor Task Inducing Motor Fatigue

Journal of motor behavior, Jan 10, 2018

To evaluate task induced motor fatigue in a well-established finger tapping task, we analyzed tap... more To evaluate task induced motor fatigue in a well-established finger tapping task, we analyzed tapping parameters and included the time course of measures of force. We hypothesized that a decline in tapping force would reflect task induced motor fatigue, defined by a lengthening of inter-tap intervals (ITI). A secondary aim was to investigate the reliability of tapping data acquisition with the force sensor. Results show that, as expected, tapping speed decreased linearly over time, due to both an increase of ITI and tap duration. In contrast, tapping force increased non-linearly over time and was uncorrelated to changes in tapping speed. Force data could serve as a measure to characterize task induced motor fatigue. Force sensors can assess a decline in tapping speed as well as an independent increase of tapping force. We argue that the increase of force reflects central compensation, i.e. perception of fatigue, due to an increase in task effort and difficulty.

Diagnostic Performance and Utility of Quantitative EEG Analyses in Delirium: Confirmatory Results From a Large Retrospective Case-Control Study

Clinical EEG and neuroscience, 2018

The lack of objective disease markers is a major cause of misdiagnosis and nonstandardized approa... more The lack of objective disease markers is a major cause of misdiagnosis and nonstandardized approaches in delirium. Recent studies conducted in well-selected patients and confined study environments suggest that quantitative electroencephalography (qEEG) can provide such markers. We hypothesize that qEEG helps remedy diagnostic uncertainty not only in well-defined study cohorts but also in a heterogeneous hospital population. In this retrospective case-control study, EEG power spectra of delirious patients and age-/gender-matched controls (n = 31 and n = 345, respectively) were fitted in a linear model to test their performance as binary classifiers. We subsequently evaluated the diagnostic performance of the best classifiers in control samples with normal EEGs (n = 534) and real-world samples including pathologic findings (n = 4294). Test reliability was estimated through split-half analyses. We found that the combination of spectral power at F3-P4 at 2 Hz (area under the curve [AUC...

Mobile electronic versus paper case report forms in clinical trials: a randomized controlled trial

BMC medical research methodology, 2017

Regulations, study design complexity and amounts of collected and shared data in clinical trials ... more Regulations, study design complexity and amounts of collected and shared data in clinical trials render efficient data handling procedures inevitable. Recent research suggests that electronic data capture can be key in this context but evidence is insufficient. This randomized controlled parallel group study tested the hypothesis that time efficiency is superior when electronic (eCRF) instead of paper case report forms (pCRF) are used for data collection. We additionally investigated predictors of time saving effects and data integrity. This study was conducted on top of a clinical weight loss trial performed at a clinical research facility over six months. All study nurses and patients participating in the clinical trial were eligible to participate and randomly allocated to enter cross-sectional data obtained during routine visits either through pCRF or eCRF. A balanced randomization list was generated before enrolment commenced. 90 and 30 records were gathered for the time that 2...

P1066: Movement preparation requires early activation of the dorsal premotor area

Clinical Neurophysiology, 2014

before and after the exercise on day 1 (T0, T1) and after the exercise on day 5 (T2). Basketball ... more before and after the exercise on day 1 (T0, T1) and after the exercise on day 5 (T2). Basketball players attended only to T0 and T1. Results: In FCR of the sedentary group (Fig. 1, amplitude ratios, blue: T0, red: T1, green: T2, bars: standard deviations), there were less short latency afferent inhibition and higher facilitation at T1 (statistically significant at ISI 35 and 50 ms). This effect decreased at T2 despite the increased success rate. Basketball players did not show a facilitation as high as that found in the sedentary group. Conclusion: Short term exercises lead to SMI changes which may function in the early phase of gaining the ability. Continued training provided higher success while the electrophysiological changes was decreasing, possibly by the conversion of the learning process into different mechanisms. Exercising already gained abilities do not produce similar SMI changes.