Publications by authors named "Tobias Brix"

31 Publications

Less severe course of COVID-19 is associated with elevated levels of antibodies against seasonal human coronaviruses OC43 and HKU1 (HCoV OC43, HCoV HKU1).

Int J Infect Dis 2021 Feb 23. Epub 2021 Feb 23.

Institute of Virology, Department of Clinical Virology, University Hospital Münster, Germany.

The clinical course of COVID-19 is very heterogeneous: Most infected individuals can be managed in an outpatient setting, but a substantial proportion of patients requires intensive care, resulting in a high rate of fatalities. We performed a biomarker study to assess the impact of prior infections with seasonal coronaviruses on COVID-19 severity. 60 patients with confirmed COVID-19 infections were included (age 30 - 82 years; 52 males, 8 females): 19 inpatients with critical disease, 16 inpatients with severe or moderate disease and 25 outpatients. Patients with critical disease had significantly lower levels of anti-HCoV OC43-NP (p = 0.016) and HCoV HKU1-NP (p = 0.023) antibodies at the first encounter compared to other COVID-19 patients. Our results indicate that prior infections with seasonal coronaviruses might protect against a severe course of disease.
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http://dx.doi.org/10.1016/j.ijid.2021.02.085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901274PMC
February 2021

Blood and cerebrospinal fluid immune cell profiles in patients with temporal lobe epilepsy of different etiologies.

Epilepsia 2020 10 7;61(10):e153-e158. Epub 2020 Sep 7.

Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.

Inflammation plays a role in the pathogenesis of immune-mediated epilepsy, but also in epilepsy of other etiology such as hippocampal sclerosis. This study aimed to characterize immune cell signatures in the peripheral blood (PB) and cerebrospinal fluid (CSF) in temporal lobe epilepsy (TLE) of different etiologies. We retrospectively evaluated CSF routine parameters and immune cell profiles using flow cytometry in a cohort of 51 patients and 45 age-matched controls with functional disorders. Groups were comprised of patients with nonlesional TLE (n = 26), TLE due to hippocampal sclerosis (n = 14), or limbic encephalitis with antibodies against the 65-kDa isoform of glutamic acid decarboxylase (GAD65-LE; n = 11). TLE patients showed increased proportions of human leukocyte antigen-DR isotype (HLA-DR)-expressing CD4 T lymphocytes in the CSF. Furthermore, they were characterized by a shift in monocyte subsets toward immature CD14 CD16 cells in the PB and blood/CSF-barrier dysfunction. Whereas TLE patients in general showed similar immune cell profiles, patients with GAD65-LE differed from other TLE patients by increased proportions of HLA-DR-expressing CD8 T lymphocytes and type 2/3 oligoclonal bands. These findings point to a role of innate and adaptive immunity in TLE. CSF parameters may help to discriminate epilepsy patients from controls and different forms of TLE from each other.
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http://dx.doi.org/10.1111/epi.16688DOI Listing
October 2020

Evaluation of openEHR Repositories Regarding Standard Compliance.

Stud Health Technol Inform 2020 Jun;270:592-596

Institute of Medical Informatics, University of Münster, Germany.

We evaluated three repositories implementing the emerging healthcare data standard openEHR for their standard compliance, completeness and vendor lock-in. We found the basic functionality to work consistently across all tested repositories. At the same time, no vendor supports the entire API yet. Some functions like template listing differ slightly in their behavior. Some vendors offer additional custom APIs that are easier to use but lead to vendor lock-in. The openEHR standard itself is designed inconsistently regarding data formats and is missing some basic functionality, for example deletion of templates. With openEHR being a young standard, these issues may be resolved in future releases.
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http://dx.doi.org/10.3233/SHTI200229DOI Listing
June 2020

Correction to: Validity of transit time-based blood pressure measurements in patients with and without heart failure or pulmonary arterial hypertension across different breathing maneuvers.

Sleep Breath 2020 09;24(3):1257-1258

Cardiovascular Medicine Division, Fondazione Toscana Gabriele Monasterio, National Research Council, CNR-Regione Toscana, Scuola Superiore San't Anna, Pisa, Italy.

After the publication of the original manuscript we found that the calculation of the supplemental data regarding the capacity of PTT-based blood pressure (BP) recordings to detect changes in systolic and diastolic BP in different cohorts of patients was incorrect. These errors occured when data were transformed from MS Excel to Sigma-Plot tables. In this correction, the affected data and the respective figures were now revised.
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http://dx.doi.org/10.1007/s11325-020-02120-2DOI Listing
September 2020

Respiratory Muscle and Lung Function in Lung Allograft Recipients: Association with Exercise Intolerance.

Respiration 2020;99(5):398-408. Epub 2020 May 13.

Respiratory Physiology Laboratory, Department of Neurology with Institute for Translational Neurology, University Hospital Münster, Münster, Germany.

Background: In lung transplant recipients (LTRs), restrictive ventilation disorder may be present due to respiratory muscle dysfunction that may reduce exercise capacity. This might be mediated by pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).

Objective: We investigated lung respiratory muscle function as well as circulating pro-inflammatory cytokines and exercise capacity in LTRs.

Methods: Fifteen LTRs (6 female, age 56 ± 14 years, 63 ± 45 months post-transplantation) and 15 healthy controls matched for age, sex, and body mass index underwent spirometry, measurement of mouth occlusion pressures, diaphragm ultrasound, and recording of twitch transdiaphragmatic (twPdi) and gastric pressures (twPgas) following magnetic stimulation of the phrenic nerves and the lower thoracic nerve roots. Exercise capacity was quantified using the 6-min walking distance (6MWD). Plasma IL-6 and TNF-α were measured using enzyme-linked immunosorbent assays.

Results: Compared with controls, patients had lower values for forced vital capacity (FVC; 81 ± 30 vs.109 ± 18% predicted, p = 0.01), maximum expiratory pressure (100 ± 21 vs.127 ± 17 cm H2O, p = 0.04), diaphragm thickening ratio (2.2 ± 0.4 vs. 3.0 ± 1.1, p = 0.01), and twPdi (10.4 ± 3.5 vs. 17.6 ± 6.7 cm H2O, p = 0.01). In LTRs, elevation of TNF-α was related to lung function (13 ± 3 vs. 11 ± 2 pg/mL in patients with FVC ≤80 vs. >80% predicted; p < 0.05), and lung function (forced expiratory volume after 1 s) was closely associated with diaphragm thickening ratio (r = 0.81; p < 0.01) and 6MWD (r = 0.63; p = 0.02).

Conclusion: There is marked restrictive ventilation disorder and respiratory muscle weakness in LTRs, especially inspiratory muscle weakness with diaphragm dysfunction. Lung function impairment relates to elevated levels of circulating TNF-α and diaphragm dysfunction and is associated with exercise intolerance.
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http://dx.doi.org/10.1159/000507264DOI Listing
May 2020

Evaluation of Respiratory Muscle Strength and Diaphragm Ultrasound: Normative Values, Theoretical Considerations, and Practical Recommendations.

Respiration 2020;99(5):369-381. Epub 2020 May 12.

Respiratory Physiology Laboratory, Department of Neurology, Institute for Translational Neurology, University Hospital Münster, Münster, Germany.

Background: Reference values derived from existing diaphragm ultrasound protocols are inconsistent, and the association between sonographic measures of diaphragm function and volitional tests of respiratory muscle strength is still ambiguous.

Objective: To propose a standardized and comprehensive protocol for diaphragm ultrasound in order to determine lower limits of normal (LLN) for both diaphragm excursion and thickness in healthy subjects and to explore the association between volitional tests of respiratory muscle strength and diaphragm ultrasound parameters.

Methods: Seventy healthy adult subjects (25 men, 45 women; age 34 ± 13 years) underwent spirometric lung function testing, determination of maximal inspiratory and expiratory pressure along with ultrasound evaluation of diaphragm excursion and thickness during tidal breathing, deep breathing, and maximum voluntary sniff. Excursion data were collected for amplitude and velocity of diaphragm displacement. Diaphragm thickness was measured in the zone of apposition at total lung capacity (TLC) and functional residual capacity (FRC). All participants underwent invasive measurement of transdiaphragmatic pressure (Pdi) during different voluntary breathing maneuvers.

Results: Ultrasound data were successfully obtained in all participants (procedure duration 12 ± 3 min). LLNs (defined as the 5th percentile) for diaphragm excursion were as follows: (a) during tidal breathing: 1.2 cm (males; M) and 1.2 cm (females; F) for amplitude, and 0.8 cm/s (M) and 0.8 cm/s (F) for velocity, (b) during maximum voluntary sniff: 2.0 cm (M) and 1.5 cm (F) for amplitude, and 6.7 (M) cm/s and 5.2 cm/s (F) for velocity, and (c) at TLC: 7.9 cm (M) and 6.4 cm (F) for amplitude. LLN for diaphragm thickness was 0.17 cm (M) and 0.15 cm (F) at FRC, and 0.46 cm (M) and 0.35 cm (F) at TLC. Values for males were consistently higher than for females, independent of age. LLN for diaphragmatic thickening ratio was 2.2 with no difference between genders. LLN for invasively measured Pdi during different breathing maneuvers are presented. Voluntary Pdi showed only weak correlation with both diaphragm excursion velocity and amplitude during forced inspiration.

Conclusions: Diaphragm ultrasound is an easy-to-perform and reproducible diagnostic tool for noninvasive assessment of diaphragm excursion and thickness. It supplements but does not replace respiratory muscle strength testing.
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http://dx.doi.org/10.1159/000506016DOI Listing
May 2020

Development and validation of prediction scores for nosocomial infections, reoperations, and adverse events in the daily clinical setting of neurosurgical patients with cerebral and spinal tumors.

J Neurosurg 2020 Mar 20:1-11. Epub 2020 Mar 20.

1Department of Neurosurgery and.

Objective: Various quality indicators are currently under investigation, aiming at measuring the quality of care in neurosurgery; however, the discipline currently lacks practical scoring systems for accurately assessing risk. The aim of this study was to develop three accurate, easy-to-use risk scoring systems for nosocomial infections, reoperations, and adverse events for patients with cerebral and spinal tumors.

Methods: The authors developed a semiautomatic registry with administrative and clinical data and included all patients with spinal or cerebral tumors treated between September 2017 and May 2019. Patients were further divided into development and validation cohorts. Multivariable logistic regression models were used to develop risk scores by assigning points based on β coefficients, and internal validation of the scores was performed.

Results: In total, 1000 patients were included. An unplanned 30-day reoperation was observed in 6.8% of patients. Nosocomial infections were documented in 7.4% of cases and any adverse event in 14.5%. The risk scores comprise variables such as emergency admission, nursing care level, ECOG performance status, and inflammatory markers on admission. Three scoring systems, NoInfECT for predicting the incidence of nosocomial infections (low risk, 1.8%; intermediate risk, 8.1%; and high risk, 26.0% [p < 0.001]), LEUCut for 30-day unplanned reoperations (low risk, 2.2%; intermediate risk, 6.8%; and high risk, 13.5% [p < 0.001]), and LINC for any adverse events (low risk, 7.6%; intermediate risk, 15.7%; and high risk, 49.5% [p < 0.001]), showed satisfactory discrimination between the different outcome groups in receiver operating characteristic curve analysis (AUC ≥ 0.7).

Conclusions: The proposed risk scores allow efficient prediction of the likelihood of adverse events, to compare quality of care between different providers, and further provide guidance to surgeons on how to allocate preoperative care.
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http://dx.doi.org/10.3171/2020.1.JNS193186DOI Listing
March 2020

Leukocyte profiles in blood and CSF distinguish neurosarcoidosis from multiple sclerosis.

J Neuroimmunol 2020 04 27;341:577171. Epub 2020 Jan 27.

Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany. Electronic address:

Distinguishing neurosarcoidosis (NS) from multiple sclerosis (MS) remains challenging and available parameters lack discriminatory power. Comprehensive flow cytometry data of blood and CSF leukocytes of patients with NS (n = 24), MS (n = 49) and idiopathic intracranial hypertension (IIH, n = 52) were analyzed by machine learning algorithms. NS featured a specific immune cell pattern with increased activated CD4+ T cells in CSF and increased plasma cells in blood. Combining blood and CSF parameters improved the differentiation. We thereby identify and independently validate a multi-dimensional model of blood and CSF supporting the difficult differential diagnosis between NS and MS.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577171DOI Listing
April 2020

Response to: Respiratory muscle dysfunction in facioscapulohumeral muscular dystrophy. Letter to the editor-reference article: sleep-related breathing disorders in facioscapulohumeral dystrophy (https://doi.org/10.1007/s11325-019-01843-1) by Santos DB et al.

Sleep Breath 2020 06 18;24(2):675-676. Epub 2019 Dec 18.

Department of Neurology with Institute of Translational Neurology, University Hospital Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany.

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http://dx.doi.org/10.1007/s11325-019-01992-3DOI Listing
June 2020

Characteristics of respiratory muscle involvement in myotonic dystrophy type 1.

Neuromuscul Disord 2020 01 5;30(1):17-27. Epub 2019 Nov 5.

Respiratory Physiology Laboratory, Institute for Sleep Medicine and Neuromuscular Disorders, University Hospital Muenster, Muenster, Germany. Electronic address:

The pathophysiology of respiratory muscle weakness in myotonic dystrophy type 1 (DM1) remains incompletely understood. 21 adult patients with DM1 (11 men, 42 ± 13 years) and 21 healthy matched controls underwent spirometry, manometry, and diaphragm ultrasound. In addition, surface electromyography of the diaphragm and the obliquus abdominis muscle was performed following cortical and posterior cervical magnetic stimulation (CMS) of the phrenic nerves or magnetic stimulation of the lower thoracic nerve roots. Magnetic stimulation was combined with invasive recording of the twitch transdiaphragmatic and gastric pressure (twPdi and twPgas) in 10 subjects per group. The following parameters were reduced in DM1 patients compared to control subjects: maximum inspiratory pressure (MIP; 40.3 ± 19.2 vs. 95.8 ± 28.5 cmHO, p < 0.01), diaphragm thickening ratio (DTR; 2.0 ± 0.4 vs. 2.7 ± 0.6, p < 0.01), twPdi following CMS (10.8 ± 8.3 vs. 21.4 ± 10.1 cmH2O, p = 0.03), and amplitude of diaphragm compound muscle action potentials (0.10 ± 0.25 vs. 0.46 ± 0.35 mV; p = 0.04). MIP and DTR were significantly correlated with the muscular impairment rating scale (MIRS) score. Maximum expiratory pressure (MEP) was reduced in DM1 patients compared to controls (41.3 ± 13.4 vs. 133.8 ± 28.0 cmH2O, p < 0.01) and showed negative correlation with the MIRS score. Pgas following a maximum cough was markedly lower in patients than in controls (71.9 ± 43.2 vs. 102.4 ± 35.5 cmHO) but without statistical significance (p = 0.06). In DM1, respiratory muscle weakness relates to clinical disease severity and involves inspiratory and probably expiratory muscle strength. Axonal phrenic nerve pathology may contribute to diaphragm dysfunction.
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http://dx.doi.org/10.1016/j.nmd.2019.10.011DOI Listing
January 2020

EMR-integrated minimal core dataset for routine health care and multiple research settings: A case study for neuroinflammatory demyelinating diseases.

PLoS One 2019 15;14(10):e0223886. Epub 2019 Oct 15.

Institute of Medical Informatics, University of Münster, Münster, Germany.

Although routine health care and clinical trials usually require the documentation of similar information, data collection is performed independently from each other, resulting in redundant documentation efforts. Standardizing routine documentation can enable secondary use for medical research. Neuroinflammatory demyelinating diseases (NIDs) represent a heterogeneous group of diseases requiring further research to improve patient management. The aim of this work is to develop, implement and evaluate a minimal core dataset in routine health care with a focus on secondary use as case study for NIDs. Therefore, a draft minimal core dataset for NIDs was created by analyzing routine, clinical trial, registry, biobank documentation and existing data standards for NIDs. Data elements (DEs) were converted into the standard format Operational Data Model, semantically annotated and analyzed via frequency analysis. The analysis produced 1958 DEs based on 864 distinct medical concepts. After review and finalization by an interdisciplinary team of neurologists, epidemiologists and medical computer scientists, the minimal core dataset (NID CDEs) consists of 46 common DEs capturing disease-specific information for reuse in the discharge letter and other research settings. It covers the areas of diagnosis, laboratory results, disease progress, expanded disability status scale, therapy and magnetic resonance imaging findings. NID CDEs was implemented in two German university hospitals and a usability study in clinical routine was conducted (participants n = 16) showing a good usability (Mean SUS = 75). From May 2017 to February 2018, 755 patients were documented with the NID CDEs, which indicates the feasibility of developing a minimal core dataset for structured documentation based on previously used documentation standards and integrating the dataset into clinical routine. By sharing, translating and reusing the minimal dataset, a transnational harmonized documentation of patients with NIDs might be realized, supporting interoperability in medical research.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223886PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6793844PMC
March 2020

Respiratory muscle weakness in facioscapulohumeral muscular dystrophy.

Muscle Nerve 2019 12 23;60(6):679-686. Epub 2019 Oct 23.

Respiratory Physiology Laboratory, Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.

Introduction: The purpose of this study was to comprehensively evaluate respiratory muscle function in adults with facioscapulohumeral muscular dystrophy (FSHD).

Methods: Fourteen patients with FSHD (9 men, 53 ± 16 years of age) and 14 matched controls underwent spirometry, diaphragm ultrasound, and measurement of twitch gastric and transdiaphragmatic pressures (twPgas and twPdi; n = 10) after magnetic stimulation of the lower thoracic nerve roots and the phrenic nerves. The latter was combined with recording of diaphragm compound muscle action potentials (CMAPs; n = 14).

Results: The following parameters were significantly lower in patients vs controls: forced vital capacity (FVC); maximum inspiratory and expiratory pressure; peak cough flow; diaphragm excursion amplitude; and thickening ratio on ultrasound, twPdi (11 ± 5 vs 20 ± 6 cmH O) and twPgas (7 ± 3 vs 25 ± 20 cmH O). Diaphragm CMAP showed no group differences. FVC correlated inversely with the clinical severity scale score (r = -0.63, P = .02).

Discussion: In FSHD, respiratory muscle weakness involves both the diaphragm and the expiratory abdominal muscles.
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http://dx.doi.org/10.1002/mus.26717DOI Listing
December 2019

Phrenic nerve involvement and respiratory muscle weakness in patients with Charcot-Marie-Tooth disease 1A.

J Peripher Nerv Syst 2019 09 29;24(3):283-293. Epub 2019 Aug 29.

Respiratory Physiology Laboratory, Department of Neurology, University of Münster, Münster, Germany.

Diaphragm weakness in Charcot-Marie-Tooth disease 1A (CMT1A) is usually associated with severe disease manifestation. This study comprehensively investigated phrenic nerve conductivity, inspiratory and expiratory muscle function in ambulatory CMT1A patients. Nineteen adults with CMT1A (13 females, 47 ± 12 years) underwent spiromanometry, diaphragm ultrasound, and magnetic stimulation of the phrenic nerves and the lower thoracic nerve roots, with recording of diaphragm compound muscle action potentials (dCMAP, n = 15), transdiaphragmatic and gastric pressures (twPdi and twPgas, n = 12). Diaphragm motor evoked potentials (dMEP, n = 15) were recorded following cortical magnetic stimulation. Patients had not been selected for respiratory complaints. Disease severity was assessed using the CMT Neuropathy Scale version 2 (CMT-NSv2). Healthy control subjects were matched for age, sex, and body mass index. The following parameters were significantly lower in CMT1A patients than in controls (all P < .05): forced vital capacity (91 ± 16 vs 110 ± 15% predicted), maximum inspiratory pressure (68 ± 22 vs 88 ± 29 cmH O), maximum expiratory pressure (91 ± 23 vs 123 ± 24 cmH O), and peak cough flow (377 ± 135 vs 492 ± 130 L/min). In CMT1A patients, dMEP and dCMAP were delayed. Patients vs controls showed lower diaphragm excursion (5 ± 2 vs 8 ± 2 cm), diaphragm thickening ratio (DTR, 1.9 [1.6-2.2] vs 2.5 [2.1-3.1]), and twPdi (8 ± 6 vs 19 ± 7 cmH O; all P < .05). DTR inversely correlated with the CMT-NSv2 score (r = -.59, P = .02). There was no group difference in twPgas following abdominal muscle stimulation. Ambulatory CMT1A patients may show phrenic nerve involvement and reduced respiratory muscle strength. Respiratory muscle weakness can be attributed to diaphragm dysfunction alone. It relates to neurological impairment and likely reflects a disease continuum.
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http://dx.doi.org/10.1111/jns.12341DOI Listing
September 2019

Noninvasive Prediction of Twitch Transdiaphragmatic Pressure: Insights from Spirometry, Diaphragm Ultrasound, and Phrenic Nerve Stimulation Studies.

Respiration 2019;98(4):301-311. Epub 2019 Aug 6.

Respiratory Physiology Laboratory, Department of Neurology with Institute for Translational Neurology, University of Muenster, Muenster, Germany.

Background: Twitch transdiaphragmatic pressure (twPdi) following magnetic stimulation (MS) of the phrenic nerves is the gold standard for non-volitional assessment of diaphragm strength. Expiratory muscle function can be investigated using MS of the abdominal muscles and measurement of twitch gastric pressure (twPgas).

Objectives: To investigate whether twitch pressures following MS of the phrenic and lower thoracic nerve roots can be predicted noninvasively by diaphragm ultrasound parameters and volitional tests of respiratory muscle strength.

Methods: Sixty-three healthy subjects underwent standard spirometry, measurement of maximum inspiratory (PImax) and expiratory pressure (PEmax), and diaphragm ultrasound. TwPdi following cervical MS of the phrenic nerve roots and twPgas after lower thoracic MS (twPgas-Thor) were measured using esophageal and gastric balloon catheters inserted transnasally. Using surface electrodes, compound muscle action potentials (CMAP) were simultaneously recorded from the diaphragm or obliquus abdominis muscles, respectively.

Results: Forced expiratory flow (FEF25-75) was significantly correlated with twPdi (r = 0.37; p = 0.003) and its components (twPgas and twitch esophageal pressure, twPes). Diaphragm excursion velocity during tidal breathing was correlated to twPes (r = 0.44; p = 0.02). No prediction of twitch pressures was possible from CMAP amplitude, forced vital capacity (FVC), or PImax. TwPgas-Thor was correlated with FEF25-75 (r = 0.46; p = 0.05) and diaphragm thickness at total lung capacity (r = 0.38; p = 0.04) but could not be predicted from CMAP amplitude, FVC, or PEmax.

Conclusions: TwPdi and twPgas-Thor cannot be predicted from volitional measures of respiratory muscle strength, diaphragm and abdominal CMAP, or diaphragm ultrasound. Invasive recording of esophageal and gastric pressures following MS remains indispensable for objective assessment of respiratory muscle strength.
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http://dx.doi.org/10.1159/000501171DOI Listing
September 2020

Assessment of Central Drive to the Diaphragm by Twitch Interpolation: Normal Values, Theoretical Considerations, and Future Directions.

Respiration 2019;98(4):283-293. Epub 2019 Jul 26.

Respiratory Physiology Laboratory, Department of Neurology with Institute for Translational Neurology, University of Münster, Münster, Germany.

Background: The twitch interpolation technique is a promising tool for assessing central drive to the diaphragm. It is used to quantify the degree of voluntary diaphragm activation during predefined breathing maneuvers.

Objectives: This study was designed to (a) determine reference values for the level of voluntary activation of the diaphragm using the twitch occlusion technique in healthy adults and (b) explore the association between central drive to the diaphragm and volitional tests of respiratory muscle strength.

Methods: Twenty-seven healthy volunteers aged 26 ± 14 years (18 male) were enrolled. Twitch transdiaphragmatic pressure (Pdi) was determined at relaxed functional residual capacity in response to cervical magnetic stimulation (CMS) of the phrenic nerves. The subjects were then instructed to gradually increase voluntary activation of the diaphragm, and the effects of superimposed magnetic stimuli on voluntary Pdi were assessed.

Results: The twitch Pdi amplitude following CMS linearly decreased with increasing inspiratory effort. The resulting diaphragm voluntary activation index (DVAI) during maximal voluntary contraction was 75 ± 15% irrespective of gender or age. Twitch duration, half relaxation time, and area under the curve of superimposed Pdi deflections did not show a linear but an exponential association with increasing voluntary activation of the diaphragm. More than 2/3 of the decrease in the above values was evident after 1/3 of voluntary diaphragm contraction. Forced vital capacity (FVC) was inversely correlated with the DVAI.

Conclusions: Twitch interpolation allows for assessment of central drive to the diaphragm. The maximum DVAI is independent of gender or age, and significantly related to FVC but not to maximum inspiratory pressure or Pdi as direct measures of diaphragm strength.
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http://dx.doi.org/10.1159/000500726DOI Listing
September 2020

The nature of respiratory muscle weakness in patients with late-onset Pompe disease.

Neuromuscul Disord 2019 08 22;29(8):618-627. Epub 2019 Jun 22.

Respiratory Physiology Laboratory, Institute for Sleep Medicine and Neuromuscular Disorders, University Hospital Muenster, Muenster, Germany. Electronic address:

Late-onset Pompe disease (LOPD) causes myopathy of skeletal and respiratory muscles, and phrenic nerve pathology putatively contributes to diaphragm weakness. The aim of this study was to investigate neural contributions to diaphragm dysfunction, usefulness of diaphragm ultrasound, and involvement of expiratory abdominal muscles in LOPD. Thirteen patients with LOPD (7 male, 51±17 years) and 13 age- and gender-matched controls underwent respiratory muscle strength testing, ultrasound evaluation of diaphragm excursion and thickness, cortical and cervical magnetic stimulation (MS) of the diaphragm with simultaneous recording of surface electromyogram and twitch transdiaphragmatic pressure (twPdi; n = 6), and MS of the abdominal muscles with recording of twitch gastric pressure (twPgas; n = 6). The following parameters were significantly reduced in LOPD patients versus controls: forced vital capacity (p<0.01), maximum inspiratory and expiratory pressure (both p<0.001), diaphragm excursion velocity (p<0.05), diaphragm thickening ratio (1.8 ± 0.4 vs. 2.6 ± 0.6, p<0.01), twPdi following cervical MS (12.0 ± 6.2 vs. 19.4 ± 4.8 cmHO, p<0.05), and twPgas following abdominal muscle stimulation (8.8 ± 8.1 vs. 34.6 ± 17.1 cmHO, p<0.01). Diaphragm motor evoked potentials and compound muscle action potentials showed no between-group differences. In conclusion, phrenic nerve involvement in LOPD could not be electrophysiologically confirmed. Ultrasound supports assessment of diaphragm function. Abdominal expiratory muscles are functionally involved in LOPD.
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http://dx.doi.org/10.1016/j.nmd.2019.06.011DOI Listing
August 2019

Seizure-induced shoulder dislocations - Case series and review of the literature.

Seizure 2019 Aug 20;70:38-42. Epub 2019 Jun 20.

Department of Neurology, University of Münster, Münster, Germany. Electronic address:

Purpose: We aimed to identify clinical characteristics of patients with shoulder dislocations caused by an epileptic seizure.

Methods: In our retrospective analysis, we identified 15 patients, recorded over an 8-year period, who were diagnosed with shoulder dislocations in the setting of a bilateral tonic-clonic seizure.

Results: Patients were almost exclusively male (13/15) and drug-naïve patients suffering their first or second seizure (14/15). Epilepsy was diagnosed in five of these 14 patients after further diagnostic tests, four patients were diagnosed with a provoked or acute symptomatic seizure and five patients with an unprovoked seizure. Treatment with anticonvulsant drugs (AED) was initiated in 10/15 patients after the first seizure, without recommendation for tapering, although long-term treatment was retrospectively judged to be appropriate for only four of those cases. Posterior dislocations - usually rare - were seen in 12/15 patients and often required complex orthopedic interventions.

Conclusions: We conclude that in particular posterior shoulder dislocations are often caused by a first seizure and should always raise the suspicion of an epileptic seizure even in the absence of a clear history. AED treatment likely has a protective effect against this type of injury, even if seizure-freedom is not achieved.
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http://dx.doi.org/10.1016/j.seizure.2019.06.025DOI Listing
August 2019

Electrophysiological Properties of the Human Diaphragm Assessed by Magnetic Phrenic Nerve Stimulation: Normal Values and Theoretical Considerations in Healthy Adults.

J Clin Neurophysiol 2019 Sep;36(5):375-384

Respiratory Physiology Laboratory, Department of Neurology with Institute for Translational Neurology, University of Muenster, Muenster, Germany.

Purpose: This study determined normal values for motor evoked potentials (MEPs) and compound muscle action potentials (CMAPs) of the diaphragm following cortical and cervical magnetic stimulation (COMS and CEMS) of the phrenic nerves in healthy adults.

Methods: Using surface electrodes, diaphragmatic MEP and CMAP were recorded in 70 subjects (34 ± 13 years, 25 men) following supramaximal cortical magnetic stimulation and CEMS at functional residual capacity and using a standardized inspiratory pressure trigger (-0.5 kPa). All healthy volunteers underwent standard spirometry and measurement of maximum inspiratory and expiratory pressure.

Results: At functional residual capacity, upper limit of normal for MEP latency was 25 ms in men and 23 ms in women (p < 0.05), and upper limit of normal for CMAP latency was 6 ms. In contrast to MEP and CMAP amplitude, corresponding latencies showed little interindividual and intraindividual variability. Use of an inspiratory pressure trigger enhanced reproducibility and amplitude of diaphragm MEP. Diaphragm responses to both cortical and cervical magnetic stimulation were symmetrical and independent of age (in our cohort), with higher values for latency and amplitude in men (each p < 0.05). Diaphragm CMAP amplitude showed weak-moderate correlations with forced vital capacity (r = 0.47; p < 0.01), maximum inspiratory pressure (r = 0.39; p < 0.01), and maximum expiratory pressure (r = 0.32; p < 0.01).

Conclusions: Combination of cortical magnetic stimulation and CEMS of the phrenic nerves is feasible and allows noninvasive assessment of both central and peripheral conductivity of the diaphragm and the inspiratory pathway.
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http://dx.doi.org/10.1097/WNP.0000000000000608DOI Listing
September 2019

Validity of transit time-based blood pressure measurements in patients with and without heart failure or pulmonary arterial hypertension across different breathing maneuvers.

Sleep Breath 2020 Mar 2;24(1):221-230. Epub 2019 May 2.

Cardiovascular Medicine Division, Fondazione Toscana Gabriele Monasterio, National Research Council, CNR-Regione Toscana, Scuola Superiore San't Anna, Pisa, Italy.

Purpose: Pulse transit time (PTT) derived by ECG and plethysmographic signal can be a promising alternative to invasive or oscillometry-based blood pressure (BP) monitoring in sleep laboratories because it does not cause arousals from sleep. Therefore, this study assessed the validity of PTT for BP monitoring under sleep laboratory-like conditions.

Methods: Ten volunteers (55.8 ± 19.6 years), 12 patients with heart failure with reduced ejection fraction (HFrEF; 67.3 ± 8.6 years), and 14 patients with Nizza class I pulmonary arterial hypertension (PAH; 59.5 ± 13.4 years) performed different breathing patterns to simulate nocturnal sleep-disordered breathing (SDB). BP was measured at least every 15 min over 1 h using oscillometry (Task Force Monitor™) and PTT (SOMNOscreen™) devices in free breathing conditions and during SDB simulation (alternating phases of hyperventilation and apneas).

Results: One hundred forty-two points of measurements were collected. No difference was found in both mean systolic BP (SBP) and diastolic BP (DBP) between oscillometric PTT-based BP measurements in the whole population and throughout the whole recording (SBP 111.3 ± 15.1 mmHg versus 110.0 ± 14.7 mmHg, p = 0.051; DBP 69.9 ± 12.2 versus 69.9 ± 14.2 mmHg, p = 0.701). Likewise, no significant difference in SBP and DBP was found between the two methods in the subgroups of healthy subjects, HFrEF patients and PAH patients, both in free breathing conditions (p > 0.05) and during SDB simulation (p > 0.05).

Conclusions: When monitoring BP in healthy subjects, and in patients with HFrEF or PAH, PTT provides a BP estimation comparable with oscillometric measurement, though slightly inaccurate, both in the condition of regular and unstable breathing.
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http://dx.doi.org/10.1007/s11325-019-01848-wDOI Listing
March 2020

Transdiapragmatic pressure and contractile properties of the diaphragm following magnetic stimulation.

Respir Physiol Neurobiol 2019 08 25;266:47-53. Epub 2019 Apr 25.

Respiratory Physiology Laboratory, Department of Neurology with Institute for Translational Neurology, University of Muenster, Muenster, Germany.

Insufficient normal values exist regarding twitch transdiaphragmatic pressure (twPdi) derived from standardized cervical and cortical magnetic stimulation (MS) of the diaphragm. Therefore, 63 subjects (24 men, 39 women; 34 ± 13 years) underwent transcortical and posterior cervical MS of the diaphragm with simultaneous recording of twitch oesophageal and gastric pressures (twPes, twPgas). Following cortical MS at functional residual capacity, twPdi amplitudes showed high intra-individual variability which was markedly reduced when an inspiratory pressure trigger was applied. Lower limit of the 95% confidence interval computed around the mean value (LLN) was 12 cmHO, independent of gender or age. Following cervical MS of the phrenic nerves, twPdi amplitudes were well reproducible and unaffected by gender, but age-dependent (age 18-30: LLN 23 cmHO; age ≥ 30: LLN 16 cmHO; p < 0.05). The inspiratory pathway can be assessed using cervical MS of the phrenic nerves. If transcranial motor cortex stimulation of the diaphragm is also applied, a standardized inspiratory pressure trigger is recommended. Dynamics of diaphragm contraction appear to be age-dependent.
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http://dx.doi.org/10.1016/j.resp.2019.04.011DOI Listing
August 2019

Sleep-related breathing disorders in facioscapulohumeral dystrophy.

Sleep Breath 2019 Sep 26;23(3):899-906. Epub 2019 Apr 26.

Department of Neurology, University Hospital Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany.

Purpose: Severe manifestations of facioscapulohumeral dystrophy (FSHD) may be associated with sleep-disordered breathing (SDB), including obstructive sleep apnea (OSA) and nocturnal hypoventilation (NH), but prevalence data are scarce. In patients with respiratory muscle weakness, detection of NH can be facilitated by transcutaneous capnometry, but respective data derived from FSHD patients have not yet been published.

Methods: We collected sleep studies and capnometry recordings from 31 adult patients with genetically confirmed FSHD who were admitted to our sleep laboratory for first-ever evaluation of sleep-related breathing. Indications for admission included non-restorative sleep, morning headache, or excessive daytime sleepiness. In addition, sleep studies were initiated if symptoms or signs of respiratory muscle weakness were present. Thirty-one subjects with insomnia served as controls for comparison of respiratory measures during sleep.

Results: In the FSHD group, 17/31 (55%) patients showed OSA and 8 (26%) had NH. NH would have been missed in 7/8 patients if only oximetry criteria of hypoventilation had been applied. Capnography results were correlated with disease severity as reflected by the Clinical Severity Score (CSS). Non-invasive ventilation (NIV) was started in 6 patients with NH and 3 individuals with OSA. Nocturnal continuous positive airway pressure was administered to 2 patients, and positional therapy was sufficient in 4 individuals. In patients initiated on NIV, nocturnal gas exchange already improved in the first night of treatment.

Conclusions: SDB is common in adult patients with FSHD complaining of sleep-related symptoms. It may comprise OSA, NH, and most often, the combination of both. Sleep-related hypercapnia is associated with disease severity. Transcutaneous capnometry is superior to pulse oximetry for detection of NH.
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http://dx.doi.org/10.1007/s11325-019-01843-1DOI Listing
September 2019

Establishing risk-adjusted quality indicators in surgery using administrative data-an example from neurosurgery.

Acta Neurochir (Wien) 2019 06 26;161(6):1057-1065. Epub 2019 Apr 26.

Department of Neurosurgery, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.

Background: The current draft of the German Hospital Structure Law requires remuneration to incorporate quality indicators. For neurosurgery, several quality indicators have been discussed, such as 30-day readmission, reoperation, or mortality rates; the rates of infections; or the length of stay. When comparing neurosurgical departments regarding these indicators, very heterogeneous patient spectrums complicate benchmarking due to the lack of risk adjustment.

Objective: In this study, we performed an analysis of quality indicators and possible risk adjustment, based only on administrative data.

Methods: All adult patients that were treated as inpatients for a brain or spinal tumour at our neurosurgical department between 2013 and 2017 were assessed for the abovementioned quality indicators. DRG-related data such as relative weight, PCCL (patient clinical complexity level), ICD-10 major diagnosis category, secondary diagnoses, age and sex were obtained. The age-adjusted Charlson Comorbidity Index (CCI) was calculated. Logistic regression analyses were performed in order to correlate quality indicators with administrative data.

Results: Overall, 2623 cases were enrolled into the study. Most patients were treated for glioma (n = 1055, 40.2%). The CCI did not correlate with the quality indicators, whereas PCCL showed a positive correlation with 30-day readmission and reoperation, SSI and nosocomial infection rates.

Conclusion: All previously discussed quality indicators are easily derived from administrative data. Administrative data alone might not be sufficient for adequate risk adjustment as they do not reflect the endogenous risk of the patient and are influenced by certain complications during inpatient stay. Appropriate concepts for risk adjustment should be compiled on the basis of prospectively designed registry studies.
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http://dx.doi.org/10.1007/s00701-018-03792-2DOI Listing
June 2019

Immune Cell Profiling of the Cerebrospinal Fluid Provides Pathogenetic Insights Into Inflammatory Neuropathies.

Front Immunol 2019 21;10:515. Epub 2019 Mar 21.

Department of Neurology, Institute of Translational Neurology, University of Münster, Münster, Germany.

Utilize immune cell profiles in the cerebrospinal fluid (CSF) to advance the understanding and potentially support the diagnosis of inflammatory neuropathies. We analyzed CSF cell flow cytometry data of patients with definite Guillain-Barré syndrome (GBS, = 26) and chronic inflammatory demyelinating polyneuropathy (CIDP, = 32) based on established diagnostic criteria in comparison to controls with relapsing-remitting multiple sclerosis (RRMS, = 49) and idiopathic intracranial hypertension (IIH, = 63). Flow cytometry revealed disease-specific changes of CSF cell composition with a significant increase of NKT cells and CD8+ T cells in CIDP, NK cells in GBS, and B cells and plasma cells in MS in comparison to IIH controls. Principal component analysis demonstrated distinct CSF immune cells pattern in inflammatory neuropathies vs. RRMS. Systematic receiver operator curve (ROC) analysis identified NKT cells as the best parameter to distinguish GBS from CIDP. Composite scores combing several of the CSF parameters differentiated inflammatory neuropathies from IIH and GBS from CIDP with high confidence. Applying a novel dimension reduction technique, we observed an intra-disease heterogeneity of inflammatory neuropathies. Inflammatory neuropathies display disease- and subtype-specific alterations of CSF cell composition. The increase of NKT cells and CD8+ T cells in CIDP and NK cells in GBS, suggests a central role of cytotoxic cell types in inflammatory neuropathies varying between acute and chronic subtypes. Composite scores constructed from multi-dimensional CSF parameters establish potential novel diagnostic tools. Intra-disease heterogeneity suggests distinct disease mechanisms in subgroups of inflammatory neuropathies.
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http://dx.doi.org/10.3389/fimmu.2019.00515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448021PMC
August 2020

Reviving 30 Year Old Technology: Lessons Learned from Transferring Patient Data Using Data Matrix Codes.

Stud Health Technol Inform 2019 ;258:90-94

Institute of Medical Informatics, University of Münster, Germany.

In patient care and medical research patient data often has to be transferred between different electronic systems. These systems can be very heterogeneous, sometimes even legacy systems, and thus, often do not support standardized interfaces for data transfer. Since nowadays barcode scanners are commonly used in clinical routine and smartphones are accessible to most patients, we implemented different interfaces based on Data Matrix codes to transfer patient data between several medical applications. Objective of this work is to show different use cases in which Data Matrix codes have been successfully applied and discuss the lessons we have learned during the process of implementation and practical usage.
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August 2019

Sleep-disordered breathing and effects of non-invasive ventilation on objective sleep and nocturnal respiration in patients with myotonic dystrophy type I.

Neuromuscul Disord 2019 04 19;29(4):302-309. Epub 2019 Feb 19.

Institute for Sleep Medicine and Neuromuscular Disorders, University Hospital Muenster, Muenster, Germany. Electronic address:

Patients with myotonic dystrophy type I (DM1) may develop nocturnal hypoventilation, requiring non-invasive ventilation. Data on long-term adherence to non-invasive ventilation, or sleep and ventilation outcomes are scarce. We retrospectively collected baseline polysomnography and capnometry results from 36 adult patients with sleep-related symptoms (42.9 ± 12.5 years, 20 female), plus follow-up sleep study records from those treated with non-invasive ventilation. Sleep-disordered breathing was found in 33 patients (91.7%) including 8 (22.2%) with daytime hypercapnia. Twenty-six patients (72.2%) showed nocturnal hypoventilation on transcutaneous capnometry. The sensitivity of oximetry to detect nocturnal hypoventilation was only 0.38. Twenty-eight patients (77.8%) showed sleep apnea, which was predominantly obstructive (n = 8), central (n = 9), or "mixed" (n = 11). Thirty-two patients were initiated on non-invasive ventilation which significantly improved ventilation and oxygenation in the first night of treatment. Follow-up revealed stable normoxia and normocapnia without deterioration of sleep outcomes for up to 52 months. Adherence to treatment was low to moderate, with substantial inter-individual variability. Sleep disordered breathing is highly prevalent in adult DM1 patients complaining of daytime sleepiness, and non-invasive ventilation significantly, rapidly and persistently improves nocturnal gas exchange. Capnometry is superior to oximetry for detection of nocturnal hypoventilation. Adherence to non-invasive ventilation remains a major issue in DM1, and long-term treatment benefits should be individually assessed.
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http://dx.doi.org/10.1016/j.nmd.2019.02.006DOI Listing
April 2019

Adverse events in brain tumor surgery: incidence, type, and impact on current quality metrics.

Acta Neurochir (Wien) 2019 02 11;161(2):287-306. Epub 2019 Jan 11.

Department of Neurosurgery, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.

Background: The aim of the study was to determine pre-operative factors associated with adverse events occurring within 30 days after neurosurgical tumor treatment in a German center, adjusting for their incidence in order to prospectively compare different centers.

Methods: Adult patients that were hospitalized due to a benign or malignant brain were retrospectively assessed for quality indicators and adverse events. Analyses were performed in order to determine risk factors for adverse events and reasons for readmission and reoperation.

Results: A total of 2511 cases were enrolled. The 30 days unplanned readmission rate to the same hospital was 5.7%. The main reason for readmission was tumor progression. Every 10th patient had an unplanned reoperation. The incidence of surgical revisions due to infections was 2.3%. Taking together all monitored adverse events, male patients had a higher risk for any of these complications (OR 1.236, 95%CI 1.025-1.490, p = 0.027). Age, sex, and histological diagnosis were predictors of experiencing any complication. Adjusted by incidence, the increased risk ratios greater than 10.0% were found for male sex, age, metastatic tumor, and hemiplegia for various quality indicators.

Conclusions: We found that most predictors of outcome rates are based on preoperative underlying medical conditions and are not modifiable by the surgeon. Comparing our results to the literature, we conclude that differences in readmission and reoperation rates are strongly influenced by standards in decision making and that comparison of outcome rates between different health-care providers on an international basis is challenging. Each health-care system has to develop own metrics for risk adjustment that require regular reassessment.
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http://dx.doi.org/10.1007/s00701-018-03790-4DOI Listing
February 2019

Connecting healthcare and clinical research: Workflow optimizations through seamless integration of EHR, pseudonymization services and EDC systems.

Int J Med Inform 2018 11 10;119:103-108. Epub 2018 Sep 10.

Institute of Medical Informatics, University of Münster, Münster, Germany. Electronic address:

Objective: In the last years, several projects promote the secondary use of routine healthcare data based on electronic health record (EHR) data. In multicenter studies, dedicated pseudonymization services are applied for unified pseudonym handling. Healthcare, clinical research and pseudonymization systems are generally disconnected. Hence, the aim of this research work is to integrate these applications and to evaluate the workflow of clinical research.

Methods: We analyzed and identified technical solutions for legislation compliant automatic pseudonym generation and for the integration into EHR as well as electronic data capture (EDC) systems. The Mainzelliste was used as pseudonymization service, which is available as open source solution and compliant with the data privacy concept in Germany. Subject of the integration was the local EHR and an in-house developed EDC system. A time and motion study was conducted to evaluate the effects on the workflow.

Results: Integration of EHR, pseudonymization service and EDC systems is technically feasible and leads to a less fragmented usage of all applications. Generated pseudonyms are obtained from the service hosted at a trusted third party and can now be used in the EDC as well as in the EHR system for direct access and re-identification. The evaluation of 90 registration iterations shows that the time for documentation has been significantly reduced in average by 39.6 s (56.3%) from 71 ± 8 s to 31 ± 5 s per registered study patient.

Conclusions: By incorporating EHR, EDC and pseudonymization systems, it is now feasible to support multicenter studies and registers out of an integrated system landscape within a hospital. Optimizing the workflow of patient registration for clinical research allows reduction of double data entry and transcription errors as well as a seamless transition from clinical routine to research data collection.
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http://dx.doi.org/10.1016/j.ijmedinf.2018.09.007DOI Listing
November 2018

ODM Data Analysis-A tool for the automatic validation, monitoring and generation of generic descriptive statistics of patient data.

PLoS One 2018 22;13(6):e0199242. Epub 2018 Jun 22.

Institute of Medical Informatics, University of Münster, Münster, Germany.

Introduction: A required step for presenting results of clinical studies is the declaration of participants demographic and baseline characteristics as claimed by the FDAAA 801. The common workflow to accomplish this task is to export the clinical data from the used electronic data capture system and import it into statistical software like SAS software or IBM SPSS. This software requires trained users, who have to implement the analysis individually for each item. These expenditures may become an obstacle for small studies. Objective of this work is to design, implement and evaluate an open source application, called ODM Data Analysis, for the semi-automatic analysis of clinical study data.

Methods: The system requires clinical data in the CDISC Operational Data Model format. After uploading the file, its syntax and data type conformity of the collected data is validated. The completeness of the study data is determined and basic statistics, including illustrative charts for each item, are generated. Datasets from four clinical studies have been used to evaluate the application's performance and functionality.

Results: The system is implemented as an open source web application (available at https://odmanalysis.uni-muenster.de) and also provided as Docker image which enables an easy distribution and installation on local systems. Study data is only stored in the application as long as the calculations are performed which is compliant with data protection endeavors. Analysis times are below half an hour, even for larger studies with over 6000 subjects.

Discussion: Medical experts have ensured the usefulness of this application to grant an overview of their collected study data for monitoring purposes and to generate descriptive statistics without further user interaction. The semi-automatic analysis has its limitations and cannot replace the complex analysis of statisticians, but it can be used as a starting point for their examination and reporting.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199242PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014674PMC
April 2019

Standardising the Development of ODM Converters: The ODMToolBox.

Stud Health Technol Inform 2018 ;247:231-235

Institute of Medical Informatics, University of Münster, Germany.

CDISC's Operational Data Model (ODM) is a flexible standard for exchanging and archiving metadata and subject clinical data in clinical trials. The Portal of Medical Data Models (MDM-Portal) uses ODM to store more than 15000 medical forms. As not every electronic health system accepts ODM as input format, there is a need for conversion between ODM and other data standards and formats. This research proposes a standardised template-based process to develop ODM converters. So far, ten converters have been developed and integrated in the MDM-Portal following this process and new ones should be included soon. The template, programming utilities and an ODM test suite have been made online available and can be used to easily develop new converters.
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June 2018

Interactive Exploration of Cosmological Dark-Matter Simulation Data.

IEEE Comput Graph Appl 2017 Mar-Apr;37(2):80-89

The winning entry of the 2015 IEEE Scientific Visualization Contest, this article describes a visualization tool for cosmological data resulting from dark-matter simulations. The proposed system helps users explore all aspects of the data at once and receive more detailed information about structures of interest at any time. Moreover, novel methods for visualizing and interactively exploring dark-matter halo substructures are proposed.
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http://dx.doi.org/10.1109/MCG.2017.20DOI Listing
September 2018