Detection of sub-nmol amounts of the antiviral drug favipiravir in 19F MRI using photo-chemically induced dynamic nuclear polarization.

In biological tissues, 19F magnetic resonance (MR) enables the non-invasive, background-free detection of 19F-containing biomarkers. However, the signal-to-noise ratio (SNR) is usually low because biomarkers are typically present at low concentrations. Measurements at low magnetic fields further reduce the SNR. In a proof-of-principal study we applied LED-based photo-chemically induced dynamic nuclear polarization (photo-CIDNP) to amplify the 19F signal at 0.6 T. For the first time, 19F MR imaging (MRI) and spectroscopy (MRS) of a fully biocompatible model system containing the antiviral drug favipiravir has been successfully performed. This fluorinated drug has been used to treat Ebola and COVID-19. Since the partially cyclic reaction scheme for photo-CIDNP allows for multiple data acquisitions, averaging further improved the SNR. The mean signal gain factor for 19F has been estimated to be in the order of 103. An in-plane resolution of 0.39 × 0.39 mm2 enabled the analysis of spatially varying degrees of hyperpolarization. The minimal detectable amount of favipiravir per voxel was estimated to about 500 pmol. The results show that 19F photo-CIDNP is a promising method for the non-invasive detection of suitable 19F-containing drugs and other compounds with very low levels of the substance.

Towards Implementation of OMOP in a German University Hospital Consortium.

BACKGROUND: In 2015, the German Federal Ministry of Education and Research initiated a large data integration and data sharing research initiative to improve the reuse of data from patient care and translational research. The Observational Medical Outcomes Partnership (OMOP) common data model and the Observational Health Data Sciences and Informatics (OHDSI) tools could be used as a core element in this initiative for harmonizing the terminologies used as well as facilitating the federation of research analyses across institutions. OBJECTIVE: To realize an OMOP/OHDSI-based pilot implementation within a consortium of eight German university hospitals, evaluate the applicability to support data harmonization and sharing among them, and identify potential enhancement requirements. METHODS: The vocabularies and terminological mapping required for importing the fact data were prepared, and the process for importing the data from the source files was designed. For eight German university hospitals, a virtual machine preconfigured with the OMOP database and the OHDSI tools as well as the jobs to import the data and conduct the analysis was provided. Last, a federated/distributed query to test the approach was executed. RESULTS: While the mapping of ICD-10 German Modification succeeded with a rate of 98.8% of all terms for diagnoses, the procedures could not be mapped and hence an extension to the OMOP standard terminologies had to be made.Overall, the data of 3 million inpatients with approximately 26 million conditions, 21 million procedures, and 23 million observations have been imported.A federated query to identify a cohort of colorectal cancer patients was successfully executed and yielded 16,701 patient cases visualized in a Sunburst plot. CONCLUSION: OMOP/OHDSI is a viable open source solution for data integration in a German research consortium. Once the terminology problems can be solved, researchers can build on an active community for further development.

SQUID-based detection of ultra-low-field multinuclear NMR of substances hyperpolarized using signal amplification by reversible exchange.

Ultra-low-field (ULF) nuclear magnetic resonance (NMR) is a promising spectroscopy method allowing for, e.g., the simultaneous detection of multiple nuclei. To overcome the low signal-to-noise ratio that usually hampers a wider application, we present here an alternative approach to ULF NMR, which makes use of the hyperpolarizing technique signal amplification by reversible exchange (SABRE). In contrast to standard parahydrogen hyperpolarization, SABRE can continuously hyperpolarize 1 H as well as other MR-active nuclei. For simultaneous measurements of 1 H and 19 F under SABRE conditions a superconducting quantum interference device (SQUID)-based NMR detection unit was adapted. We successfully hyperpolarized fluorinated pyridine derivatives with an up to 2000-fold signal enhancement in 19 F. The detected signals may be explained by two alternative reaction mechanisms. SABRE combined with simultaneous SQUID-based broadband multinuclear detection may enable the quantitative analysis of multinuclear processes.

[Completeness and quality of baseline data and follow-up in cancer registry--an analysis on the example of colorectal cancer]. / Vollständigkeit und Qualität der Basisdaten und der Nachbeobachtung im Krebsregister--Eine Untersuchung am Beispiel des kolorektalen Karzinoms.

BACKGROUND AND AIM: In Germany, data of cancer patients are recorded not only in epidemiological registers but also in clinical cancer registers. To ensure the networking of all included medical partners, quality control, and clinical research it is necessary that cancer cases are captured more or less completely. The aim of the present study was to compare the data sets of two registers. PATIENTS AND METHODS: Data from patients with colorectal cancer from two large surgical clinics in Magdeburg are recorded in two registers - the Clinical Cancer Registry Magdeburg and the Institute of Quality Assurance in Operative Medicine at the Otto-von-Guericke University Magdeburg. Here we compared the data sets in order to check the completeness of data capturing and to determine factors influencing the degree of completeness. RESULTS: From all patients captured in the Institute of Quality Assurance, 78.9% are found also in the clinical cancer registry. The percentage improves over the course of time, but also depends on diagnostic criteria such as the staging. There are some differences between both registries, explainable by their specific objectives. Particularly, it is demonstrated that incomplete follow-up record may bias estimates of survival rates from registries. CONCLUSION: Ensuring the completeness and correctness of data is a major challenge for cancer registries. It has distinct influence on estimated quality parameters such as survival rates.

Gadolinium-enhanced magnetic resonance angiography in brain death.

Confirmatory tests for the diagnosis of brain death in addition to clinical findings may shorten observation time required in some countries and may add certainty to the diagnosis under specific circumstances. The practicability of Gadolinium-enhanced magnetic resonance angiography to confirm cerebral circulatory arrest was assessed after the diagnosis of brain death in 15 patients using a 1.5 Tesla MRI scanner. In all 15 patients extracranial blood flow distal to the external carotid arteries was undisturbed. In 14 patients no contrast medium was noted within intracerebral vessels above the proximal level of the intracerebral arteries. In one patient more distal segments of the anterior and middle cerebral arteries (A3 and M3) were filled with contrast medium. Gadolinium-enhanced MRA may be considered conclusive evidence of cerebral circulatory arrest, when major intracranial vessels fail to fill with contrast medium while extracranial vessels show normal blood flow.

The impact of physiological noise correction on fMRI at 7 T.

Cognitive neuroimaging studies typically require fast whole brain image acquisition with maximal sensitivity to small BOLD signal changes. To increase the sensitivity, higher field strengths are often employed, since they provide an increased image signal-to-noise ratio (SNR). However, as image SNR increases, the relative contribution of physiological noise to the total time series noise will be greater compared to that from thermal noise. At 7 T, we studied how the physiological noise contribution can be best reduced for EPI time series acquired at three different spatial resolutions (1.1 mm × 1.1 mm × 1.8 mm, 2 mm × 2 mm × 2 mm and 3 mm × 3 mm × 3 mm). Applying optimal physiological noise correction methods improved temporal SNR (tSNR) and increased the numbers of significantly activated voxels in fMRI visual activation studies for all sets of acquisition parameters. The most dramatic results were achieved for the lowest spatial resolution, an acquisition parameter combination commonly used in cognitive neuroimaging which requires high functional sensitivity and temporal resolution (i.e. 3mm isotropic resolution and whole brain image repetition time of 2s). For this data, physiological noise models based on cardio-respiratory information improved tSNR by approximately 25% in the visual cortex and 35% sub-cortically. When the time series were additionally corrected for the residual effects of head motion after retrospective realignment, the tSNR was increased by around 58% in the visual cortex and 71% sub-cortically, exceeding tSNR ~140. In conclusion, optimal physiological noise correction at 7 T increases tSNR significantly, resulting in the highest tSNR per unit time published so far. This tSNR improvement translates into a significant increase in BOLD sensitivity, facilitating the study of even subtle BOLD responses.

[Test-retest reliability of a web-based colour vision test]. / Untersuchungen zur Re-Test Reliabilität eines webbasierten Farbsehtests.

BACKGROUND: Screening tests should be simple, with high acceptance, low costs and offer a high sensitivity and specificity as well as high reliability. The test-retest reliability of a web-based colour vision test was evaluated. METHOD: The results of 386 subjects, who had performed the web-based colour vision test with 25 colour plates twice (available at http://www.farbsehtest.de), were analysed from an mySQL data base. Retests were performed spontaneously, normally on the same day, or through an email newsletter with a request to repeat the test. Test-retest reliability was assessed by calculating the kappa coefficient and the corresponding confidence interval. The McNemar test was used as a complementary procedure to detect the presence of systematic differences between test results. RESULTS: The kappa coefficient rises with increasing time interval between the first test performance and the test repetition. Thus it was 0.24 when the test was repeated within one hour (confidence interval 0.07 - 0.41, n = 63), it increases to 0.83 (confidence interval 0.75 - 0.92, n = 240) in the subjects who repeated the test at the earliest after two years. While the proportion of failed tests (< 3 mistakes) in the second test performance markedly decreases when the test is repeated in the short term within one hour (p < 0.001, McNemar), we were unable to identify any systematic differences (p = 0.602) for a time interval of more than one day. CONCLUSIONS: The web-based colour vision test is a reliable screening test with good reproducible results as well under uncontrolled examination conditions. Subjects must perform the test with serious intent and should not aim at a positive test result by training or manipulation because of self-delusion. Test results are reliable if the time interval between test and retest is more than one day.

Alcohol induced region-dependent alterations of hemodynamic response: implications for the statistical interpretation of pharmacological fMRI studies.

Worldwide, ethanol abuse causes thousands of fatal accidents annually as well as innumerable social dysfunctions and severe medical disorders. Yet, few studies have used the blood oxygenation level dependent functional magnetic resonance imaging method (BOLD fMRI) to map how alcohol alters brain functions, as fMRI relies on neurovascular coupling, which may change due to the vasoactive properties of alcohol. We monitored the hemodynamic response function (HRF) with a high temporal resolution. In both motor cortices and the visual cortex, alcohol prolonged the time course of the HRF, indicating an overall slow-down of neurovascular coupling rather than an isolated reduction in neuronal activity. However, in the supplementary motor area, alcohol-induced changes to the HRF suggest a reduced neuronal activation. This may explain why initiating and coordinating complex movements, including speech production, are often impaired earlier than executing basic motor patterns. Furthermore, the present study revealed a potential pitfall associated with the statistical interpretation of pharmacological fMRI studies based on the general linear model: if the functional form of the HRF is changed between the conditions data may be erroneously interpreted as increased or decreased neuronal activation. Thus, our study not only presents an additional key to how alcohol affects the network of brain functions but also implies that potential changes to neurovascular coupling have to be taken into account when interpreting BOLD fMRI. Therefore, measuring individual drug-induced HRF changes is recommended for pharmacological fMRI.

A new concept of a unified parameter management, experiment control, and data analysis in fMRI: application to real-time fMRI at 3T and 7T.

In functional MRI (fMRI) complex experiments and applications require increasingly complex parameter handling as the experimental setup usually consists of separated soft- and hardware systems. Advanced real-time applications such as neurofeedback-based training or brain computer interfaces (BCIs) may even require adaptive changes of the paradigms and experimental setup during the measurement. This would be facilitated by an automated management of the overall workflow and a control of the communication between all experimental components. We realized a concept based on an XML software framework called Experiment Description Language (EDL). All parameters relevant for real-time data acquisition, real-time fMRI (rtfMRI) statistical data analysis, stimulus presentation, and activation processing are stored in one central EDL file, and processed during the experiment. A usability study comparing the central EDL parameter management with traditional approaches showed an improvement of the complete experimental handling. Based on this concept, a feasibility study realizing a dynamic rtfMRI-based brain computer interface showed that the developed system in combination with EDL was able to reliably detect and evaluate activation patterns in real-time. The implementation of a centrally controlled communication between the subsystems involved in the rtfMRI experiments reduced potential inconsistencies, and will open new applications for adaptive BCIs.

[Validity of a web-based color vision test for screening examinations of color vision]. / Untersuchungen zur Validität eines webbasierten Farbsehtests für Screeninguntersuchungen des Farbensehens.

BACKGROUND: With standardized examination conditions, a web-based color vision test using pseudoisochromatic color plates can deliver test results comparable to those yielded by conventional color vision tests. The aim of the study is to analyze to what extent a web-based color vision test can be used as a screening test on the internet after visual monitor calibration. METHODS: A German-language web-based color vision test with 25 pseudoisochromatic color plates based on the color plates of Velhagen and Broschmann and of Ishihara was developed, which can be seen at http://www.farbsehtest.de. Volunteers were recruited by means of specific information distributed on the internet, in various print media, and on the radio. RESULTS: Over a period of 12 months, 2,126 of the initial volunteers [541 women and 1,588 men; mean age 34.27 (+/-14.1) years] with a valid test result for 25 color plates performed the web-based color vision test, 1,700 (506 women and 1,194 men) of whom passed it. Of the 426 volunteers who did not pass the test, 32 were women and 394, men. Counter-testing was performed on 101 volunteers (34 women and 67 men) with a mean age of 36.74 (+/-11.6) years. CONCLUSIONS: The results recorded in the patients who underwent counter-testing suggest that, if handled correctly, the web-based color vision test can be used as a color vision screening test on the internet.

[Virtual microscopy and digital pathology]. / Virtuelle Mikroskopie und digitale Pathologie.

Virtual microscopy has advanced considerably and is bound to be integrated into routine diagnostics in the very near future. Its integration into existing information systems builds up digital pathology. In this review, we present details, advantages and limitations of this novel technology and describe solutions regarding its adaptation to routine workflow. The chief aim is to define an uniform data format for virtual specimens to guarantee an interoperability between different systems. In the long term, digital archives and networks will be established that will allow for a worldwide access to virtual specimens.

In vivo 1H magnetic resonance spectroscopy of rat brain after valproate administration.

Previous studies have shown that valproate is detectable in vitro by 1H magnetic resonance spectroscopy (MRS) at 1.5 T, whereas in patients on valproate monotherapy, no significant dose-dependent valproate signal could be seen. To investigate whether an increased signal-to-noise ratio as provided by higher valproate doses and increased magnetic field strength would enable detection of valproate in vivo, six Wistar rats were examined using volume-selective 1H MRS at 2.34 T. The spectra were analyzed by fitting a linear superposition of the basis spectra of valproate, brain metabolites, and simulated lipid signals. The analysis revealed no significant signal contributions after valproate administration of up to 330 mg/kg body weight. To analyze how underlying mechanisms, such as potential drug interactions with macromolecules, may affect the valproate signal, additional in vitro spectra of valproate were measured before and after adding albumin. The spectra exhibited a strong decrease of the valproate signal with increasing albumin concentration. The results support the hypothesis that in vivo valproate is bound to a high degree to macromolecules and will therefore not be detectable by 1H MRS.

Navigated diffusion-weighted imaging with interpolated phase-correction for high-resolution imaging of stroke.

Stroke imaging was revolutionised with the introduction of diffusion-weighted MRI (DWI). The commonly used echoplanar DWI suffers from geometrical distortion near the skull base and the frontal regions and from reduced spatial resolution and fat suppression. To allow a voxel-by-voxel comparison between high-resolution spin-echo images, we implemented spin-echo-based DWI. Motion artefacts were eliminated by phase correction in hybrid frequency-Fourier domain using navigator echoes. In a novel approach, distorted navigator echoes which did not eliminate motion artefacts were replaced with interpolated navigator echoes, leading to restored image information. Navigated DWI yielded high-resolution images in 21 of 24 patients with brain ischaemia, allowing diagnosis of even small or diffuse zones of ischaemia. We determined the spatial distribution and mean of T(2)- and DWI signal intensity and apparent diffusion coefficients (ADC), using a multidimensional histogram-based analysis. Mean ADC were decreased in ischaemic areas less than 9 days old. The technique may also be useful for high-resolution DWI of tissue other than the brain.

Volume-selective 1H MR spectroscopy for in vivo detection of valproate in patients with epilepsy.

We performed volume-selective 1H MR spectroscopy (1H-MRS) on 12 patients on valproate monotherapy to detect valproate in vivo in the brain. We also acquired reference valproate spectra in vitro in subphysiological 15 g/l albumin solution in saline, in which valproate showed two resonance peaks at 0.7 and 1.2 ppm and a minimum detection threshold of 240 mg/l. In vivo 1H-MRS spectra in brain showed peaks between 0.6 and 1.6 ppm. Simultaneous serum valproate concentrations did not correlate with these integrated MRS peaks. On follow-up, changes in these signals also did not correlate with increasing serum valproate levels. The inconsistency of in vivo 1H-MRS signals at varying serum levels and the high detection levels in vitro suggest that valproate signals are missed in vivo because valproate is metabolised or strongly bound, presumably to brain macromolecules.

Intracerebral pH affects the T2 relaxation time of brain tissue.

Signal changes in activated brain areas are detectable by MRI and MR spectroscopy (MRS). Shifts in pH occur during brain activation. Our aim was to investigate the relationship between changes in pH and T2 relaxation times. T2 was determined in vitro at 24 MHz in various liquids at different pH using a Carr-Purcell-Meiboom-Gill (CPMG) spin-echo sequence. We also studied five Fisher rats were studied at 2.4 tesla with a double-tuneable surface coil. After baseline measurements, potassium cyanide was injected, producing intracerebral acidosis. Alternating series of 1H CPMG spin-echo sequences and 31P spectra were acquired. True T2 relaxation times were calculated from a CPMG multi-echo train. Changes in intracellular pH determined from 31P spectra. In vitro measurements demonstrated a correlation between T2 and pH that could be described by a quadratic fit curve. Depending on the initial pH, changes of 0.2 induced changes in T2 of up to 150 ms. In vivo measurements confirmed these findings. After intraperitoneal injection of a sublethal dose of cyanide, T2 decreased by about 5% in four cases, followed by recovery after 2 h. The in vitro measurements demonstrated that changes in pH can lead to significant signal change on T2- or T2*- weighted images. The dependence of T2 on pH in vitro was confirmed in vivo; it may contribute to signal change in activated brain areas.

[Standards for safe data exchange in teleradiology exemplified by image and report distribution]. / Standards für den sicheren Datenaustausch in der Teleradiologie am Beispiel der Bild- und Befundverteilung.

The use of telemedicine is becoming indispensable for a continuous and economical delivery of a high quality of care. However, data protection requirements have to be considered. For the selection of solutions, vendor-independent components based on standards are a prerequisite for a seamless integration into the existing, often heterogeneous, IT infrastructure. The "Internet protocol" TCP/IP and the DICOM standard with it's new security extensions form the basis for an internationally standardized and accepted procedure for a secure interchange of radiological images beyond platform boundaries.

A JAVA-based DICOM server with integration of clinical findings and DICOM-conform data encryption.

The transfer of large amounts of medical data within heterogeneous hard and software infrastructures and the exploitation of distributed resources require a fast, secure, and platform-independent data exchange. To avoid costly vendor-specific solutions, a DICOM server was implemented in JAVA. Data access was enabled via internet browser technology. Relevant patient and image acquisition information was extracted from the DICOM images and stored into a relational database. Patient information such as radiological findings were transferred from the Radiological Information System into the database. Image data were accessed either by a fast preview tool or using a JAVA-based DICOM viewer. Since data security mechanisms are not yet part of the DICOM standard, a DICOM-conform encryption of sensitive patient data was implemented. The method allowed a dynamic selection of the data to be encrypted. Integrating this module into the image server enabled the fast and secure transfer of image data across insecure networks as well as long-term storage on CD-Recordables.

Concepts and data model for a co-operative neurovascular database.

BACKGROUND: Problems of clinical management of neurovascular diseases are very complex. This is caused by the chronic character of the diseases, a long history of symptoms and diverse treatments. If patients are to benefit from treatment, then treatment decisions have to rely on reliable and accurate knowledge of the natural history of the disease and the various treatments. METHODS: Recent developments in statistical methodology and experience from electronic patient records are used to establish an information infrastructure based on a centralized register. RESULTS: A protocol to collect data on neurovascular diseases with technical as well as logistical aspects of implementing a database for neurovascular diseases are described. The database is designed as a co-operative tool of audit and research available to co-operating centres. CONCLUSION: When a database is linked to a systematic patient follow-up, it can be used to study prognosis. Careful analysis of patient outcome is valuable for decision-making.

Simulation and analysis of magnetic resonance elastography wave images using coupled harmonic oscillators and Gaussian local frequency estimation.

New methods for simulating and analyzing Magnetic Resonance Elastography (MRE) images are introduced. To simulate a two-dimensional shear wave pattern, the wave equation is solved for a field of coupled harmonic oscillators with spatially varying coupling and damping coefficients in the presence of an external force. The spatial distribution of the coupling and the damping constants are derived from an MR image of the investigated object. To validate the simulation as well as to derive the elasticity modules from experimental MRE images, the wave patterns are analyzed using a Local Frequency Estimation (LFE) algorithm based on Gauss filter functions with variable bandwidths. The algorithms are tested using an Agar gel phantom with spatially varying elasticity constants. Simulated wave patterns and LFE results show a high agreement with experimental data. Furthermore, brain images with estimated elasticities for gray and white matter as well as for exemplary tumor tissue are used to simulate experimental MRE data. The calculations show that already small distributions of pathologically changed brain tissue should be detectable by MRE even within the limit of relatively low shear wave excitation frequency around 0.2 kHz.