Shimon Vega in the eyes of his students and postdocs.

Professor Shimon Vega (1943-2021) of the Weizmann Institute of Science passed away on the 16-th of November. Shimon Vega established theoretical frameworks to develop and explain solid-state nuclear magnetic resonance (NMR) and dynamic nuclear polarization (DNP) techniques and methodologies. His departure left a profound mark on his many students, postdocs, and colleagues. Shortly after his passing, we all assembled spontaneously for an international online meeting to share our reflections and memories of our experiences in Shimon's lab and how they affected us deeply during that period of timeand throughout our scientific careers. These thoughts and feelings were put here into writing.

Viscoelastic power law parameters of in vivo human brain estimated by MR elastography.

The noninvasive imaging technique of magnetic resonance elastography (MRE) was used to estimate the power law behavior of the viscoelastic properties of the human brain in vivo. The mechanical properties for four volunteers are investigated using shear waves induced over a frequency range of 10-50Hz to produce a displacement field measured by magnetic resonance motion-encoding gradients. The average storage modulus (µR) reconstructed with non-linear inversion (NLI) increased from approximately 0.95 to 2.58kPa over the 10-50Hz span; the average loss modulus (µI) also increased from 0.29 to 1.25kPa over the range. These increases were modeled by independent power law (PL) relations for µR and µI returning whole brain, group mean exponent values of 0.88 and 1.07 respectively. Investigation of these exponents also showed distinctly different behavior in the region of the cerebral falx compared to other brain structures.

The simulation of magnetic resonance elastography through atherosclerosis.

The clinical diagnosis of atherosclerosis via the measurement of stenosis size is widely acknowledged as an imperfect criterion. The vulnerability of an atherosclerotic plaque to rupture is associated with its mechanical properties. The potential to image these mechanical properties using magnetic resonance elastography (MRE) was investigated through synthetic datasets. An image of the steady state wave propagation, equivalent to the first harmonic, can be extracted directly from finite element analysis. Inversion of this displacement data yields a map of the shear modulus, known as an elastogram. The variation of plaque composition, stenosis size, Gaussian noise, filter thresholds and excitation frequency were explored. A decreasing mean shear modulus with an increasing lipid composition was identified through all stenosis sizes. However the inversion algorithm showed sensitivity to parameter variation leading to artefacts which disrupted both the elastograms and quantitative trends. As noise was increased up to a realistic level, the contrast was maintained between the fully fibrous and lipid plaques but lost between the interim compositions. Although incorporating a Butterworth filter improved the performance of the algorithm, restrictive filter thresholds resulted in a reduction of the sensitivity of the algorithm to composition and noise variation. Increasing the excitation frequency improved the techniques ability to image the magnitude of the shear modulus and identify a contrast between compositions. In conclusion, whilst the technique has the potential to image the shear modulus of atherosclerotic plaques, future research will require the integration of a heterogeneous inversion algorithm.

High Resolution Imaging of Viscoelastic Properties of Intracranial Tumours by Multi-Frequency Magnetic Resonance Elastography.

PURPOSE: In recent years Magnetic Resonance Elastography (MRE) emerged into a clinically applicable imaging technique. It has been shown that MRE is capable of measuring global changes of the viscoelastic properties of cerebral tissue. The purpose of our study was to evaluate a spatially resolved three-dimensional multi-frequent MRE (3DMMRE) for assessment of the viscoelastic properties of intracranial tumours. METHODS: A total of 27 patients (63 ± 13 years) were included. All examinations were performed on a 3.0 T scanner, using a modified phase-contrast echo planar imaging sequence. We used 7 vibration frequencies in the low acoustic range with a temporal resolution of 8 dynamics per wave cycle. Post-processing included multi-frequency dual elasto-visco (MDEV) inversion to generate high-resolution maps of the magnitude |G*| and the phase angle φ of the complex valued shear modulus. RESULTS: The tumour entities included in this study were: glioblastoma (n = 11), anaplastic astrocytoma (n = 3), meningioma (n = 7), cerebral metastasis (n = 5) and intracerebral abscess formation (n = 1). Primary brain tumours and cerebral metastases were not distinguishable in terms of |G*| and φ. Glioblastoma presented the largest range of |G*| values and a trend was delineable that glioblastoma were slightly softer than WHO grade III tumours. In terms of φ, meningiomas were clearly distinguishable from all other entities. CONCLUSIONS: In this pilot study, while analysing the viscoelastic constants of various intracranial tumour entities with an improved spatial resolution, it was possible to characterize intracranial tumours by their mechanical properties. We were able to clearly delineate meningiomas from intraaxial tumours, while for the latter group an overlap remains in viscoelastic terms.

Diffusion tensor imaging in amyotrophic lateral sclerosis--increased sensitivity with optimized region-of-interest delineation.

PURPOSE: Diagnosis of amyotrophic lateral sclerosis (ALS) can be difficult from clinical symptoms alone. Diffusion tensor imaging (DTI) has been suggested as an adjunct diagnostic method. DTI parameter changes have been repeatedly demonstrated, especially in the corticospinal tract (CST) as the predominantly affected structure. However, a recent meta-analysis reported only a modest discriminatory capability, questioning the value of this method as a confirmatory test in single subjects with suspected ALS. We investigated how methodological differences in CST delineation influence the discriminatory capability. METHODS: DTI data were acquired in 13 ALS patients and an age-matched healthy control group. We calculated and compared receiver operation characteristic (ROC) curves of four different analysis methods using either a manual or an atlas-based region of interest (ROI) of the CST in combination with and without tract-based spatial statistics (TBSS). RESULTS: The analysis method combining atlas-based ROIs with TBSS yielded an area under the curve (AUC) of 0.936 and a sensitivity and specificity of 100 % and 91.67 %. These are the best results among the four analysis methods evaluated: manual ROIs (AUC = 0.846, sensitivity: 69.23, specificity: 91.67), atlas-based ROIs alone (AUC = 0.917, sensitivity: 76.92, specificity: 91.67), manual ROIs in combination with TBSS (AUC = 0.885, sensitivity: 76.92, specificity: 91.67). CONCLUSIONS: Sensitivity and specificity strongly depend on the CST delineation approach. The combination of an atlas-based ROI with TBSS is a promising fully automatic method with improved discriminatory capability compared to other approaches. It could ultimately serve as a confirmatory test in single ALS patients.

Patient-activated three-dimensional multifrequency magnetic resonance elastography for high-resolution mechanical imaging of the liver and spleen.

PURPOSE: To introduce a novel in-vivo three-dimensional multifrequency magnetic resonance elastography (3D-MMRE) method for high-resolution mechanical characterization of the liver and spleen. MATERIALS AND METHODS: Ten healthy volunteers were examined by abdominal single-shot 3D-MMRE using a novel patient-activated trigger system with respiratory control. 10 contiguous slices with 2.5  mm cubic voxel resolution, 3 wave components, 8 time steps, and 2 averages were acquired at 7 mechanical excitation frequencies from 30 to 60  Hz. The total imaging time was approximately 15  min. For postprocessing, multifrequency dual elasto-visco (MDEV) inversion was used to calculate high-resolution mechanical parameter maps of the abdomen including the liver and spleen. RESULTS: Two parameters maps were generated from each image slice to capture the magnitude and the phase angle of the complex shear modulus. Both parameters depicted the mechanical structures of the abdomen with unprecedented high spatial resolution. Spatially averaged group mean values of the liver and spleen are 1.27 ±â€Š0.17 kPa and 2.01 ±â€Š0.69 kPa, indicating a significantly higher asymptomatic stiffness of the spleen compared to the liver. CONCLUSION: Patient-activated respiratory-gated 3D-MMRE combined with MDEV inversion provides highly resolved mechanical maps of the liver and spleen that are superior to previous elastograms measured by abdominal MRE.

Characterization of focal breast lesions by means of elastography.

PURPOSE: The modern method of sonoelastography of the breast is used for differentiating focal lesions. This review gives an overview of the different techniques available and discusses their roles in the routine clinical setting. MATERIALS AND METHODS: The presented techniques include compression or vibration elastography as well as shear wave elastography. Descriptions of the methods are supplemented by a discussion of the clinical role of each technique based on the most recent literature. We discuss by outlining two recent experimental approaches - MRI and tomosynthesis elastography. RESULTS: Currently available data suggest that elastography is an important supplementary tool for the differentiation of breast tumors under routine clinical conditions. The specificity improves with the immediate availability of additional diagnostic information using real-time techniques and/or the calculation of strain ratios (SR). Elastography is especially helpful in women with involuted breasts for differentiating BI-RADS-US 3 and 4 lesions and for evaluating very small cancers without the typical imaging features of malignancy. Here, elastography techniques are highly specific, while the sensitivity decreases compared to B-mode ultrasound. SR calculation is especially helpful in women who have a high risk of breast cancer and high pretest likelihood. CONCLUSION: B-mode ultrasound is still the first-line method for the initial evaluation of the breast. If suspicious findings are detected, elastography with or without SR calculation is the most crucial supplementary tool.

[Magnetic resonance elastography 2.0: high resolution imaging of soft tissue elasticity, viscosity and pressure]. / Magnetresonanzelastographie 2.0: Hochaufgelöste Bildgebung zur Bestimmung von Elastizität, Viskosität und Druck weicher Gewebe.

Elastography is the image-based measurement of the viscoelastic properties of soft biological tissues. Diseases such as fibrosis, tumors, or hypertension significantly alter the mechanical properties of tissues. These changes are highly sensitive to manual palpation. This article reviews new methods of magnetic resonance elastography (MRE) and their potential clinical applications. Furthermore, this article discusses pilot studies investigating pressure- and compression-sensitive MRE of the heart, the liver, and the brain. New developments in three-dimensional multifrequency MRE have the potential for generating highly resolved maps of viscoelastic tissue properties. Such maps are a new source of radiological information that sensitively reflects the micromechanical structure of a biological tissue.).

Viscoelasticity-based magnetic resonance elastography for the assessment of liver fibrosis in hepatitis C patients after liver transplantation.

PURPOSE: Despite advantages in antiviral therapy of hepatitis C (HCV) in recent years, progressing liver fibrosis remains a major problem for patients suffering from hepatitis C after liver transplantation. Therefore, effective non-invasive methods for the assessment of liver fibrosis are needed in order to guide treatment decisions and predict prognosis in these patients. The aim of this study was to prospectively assess the diagnostic accuracy of viscoelasticity-based magnetic resonance (MR) elastography for the assessment of liver fibrosis in HCV patients after liver transplantation. MATERIALS AND METHODS: After IRB approval, a total of 25 patients, who had received a liver graft due to chronic hepatitis C underwent both liver biopsy and MR elastography. Two viscoelastic constants, the shear elasticity µ and the powerlaw exponent α were calculated by fitting the frequency function of the complex shear modulus with the viscoelastic springpot-model. RESULTS: A strong positive correlation between shear elasticity µ and the stage of fibrosis could be found (R = 0.486, p = 0.0136). The area under the receiver operating curve (AUROC) of MR elastography based on µ for diagnosis of severe fibrosis (F ≥ 3) was 0.87 and 0.65 for diagnosis of significant fibrosis (F ≥ 2). The powerlaw exponent α did not correlate with the stage of fibrosis. CONCLUSION: MR elastography represents a promising non-invasive procedure for the assessment of higher grades of fibrosis in HCV patients after liver transplantation. The poor correlation for lower grades of fibrosis suggests unknown mechanical interactions in the transplanted liver.

[Magnetic resonance elastography of the liver]. / Magnetresonanzelastographie der Leber.

CLINICAL/METHODICAL ISSUE: The early detection of liver fibrosis remains a major challenge in medical imaging. STANDARD RADIOLOGICAL METHODS: Nowadays staging of liver fibrosis is not a task for radiological examinations and the gold standard is liver puncture. METHODICAL INNOVATIONS: Elastography is sensitive to the mechanical properties of soft tissues and in the liver stiffness is highly correlated to the degree of fibrosis. In magnetic resonance imaging elastography (MRE) time-harmonic vibrations are induced in the liver and encoded by motion-sensitive phase-contrast sequences. Viscoelastic constants are recovered from the obtained wave images and displayed by so-called elastograms. PERFORMANCE: The MRE procedure is able to discriminate low grades of fibrosis (F0-F1) from medium and severe fibrosis (F2-F4) with a diagnostic accuracy (AUROC) of 0.92. ACHIEVEMENTS: Currently, MRE is the most sensitive imaging modality for the noninvasive staging of liver fibrosis. PRACTICAL RECOMMENDATIONS: Current technical developments of MRE may further improve the accuracy of the method towards a new gold standard for noninvasive staging of fibrosis by radiologists.

Measurement of the hyperelastic properties of ex vivo brain tissue slices.

The elastic and hyperelastic properties of brain tissue are of interest to the medical research community as there are several applications where accurate characterization of these properties is crucial for an accurate outcome. The linear response is applicable to brain elastography, while the non-linear response is of interest for surgical simulation programs. Because of the biological differences between gray and white matter, it is reasonable to expect a difference in their mechanical properties. The goal of this work is to characterize the elastic and hyperelastic properties of the brain gray and white matter. In this method, force-displacement data of these tissues were acquired from 25 different brain samples using an indentation apparatus. These data were processed with an inverse problem algorithm using finite element method as the forward problem solver. Young's modulus and the hyperelastic parameters corresponding to the commonly used Polynomial, Yeoh, Arruda-Boyce, and Ogden models were obtained. The parameters characterizing the linear and non-linear mechanical behavior of gray and white matters were found to be significantly different. Young's modulus was 1787±186 and 1195±157Pa for white matter and gray matter, respectively. Among hyperelastic models, due to its accuracy, fewer parameters and shorter computational time requirements, Yeoh model was found to be the most suitable. Due to the significant differences between the linear and non-linear tissue response, we conclude that incorporating these differences into brain biomechanical models is necessary to increase accuracy.

Patient-specific electronic decision support reduces prescription of excessive doses.

OBJECTIVES: Prescription of excessive doses is the most common prescription error, provoking dose-dependent adverse drug reactions. Clinical decision support systems (CDSS) can prevent prescription errors especially when mainly clinically relevant warnings are issued. We have built and evaluated a CDSS providing upper dose limits personalised to individual patient characteristics thus guaranteeing for specific warnings. METHODS: For 170 compounds, detailed information on upper dose limits (according to the drug label) was compiled. A comprehensive software-algorithm extracted relevant patient information from the electronic chart (eg, age, renal function, comedication). The CDSS was integrated into the local prescribing platform for outpatients and patients at discharge, providing immediate dosage feedback. Its impact was evaluated in a 90-day intervention study (phase 1: baseline; phase 2: intervention). Outcome measures were frequency of excessive doses before and after intervention considering potential induction of new medication errors. Moreover, predictors for alert adherence were analysed. RESULTS: In phase 1, 552 of 12,197 (4.5%) prescriptions exceeded upper dose limits. In phase 2, initially 559 warnings were triggered (4.8%, p=0.37). Physicians were responsive to one in four warnings mostly adjusting dosages. Thus, the final prescription rate of excessive doses was reduced to 3.6%, with 20% less excessive doses compared with baseline (p<0.001). No new manifest prescription errors were induced. Physicians' alert adherence correlated with patients' age, prescribed drug class, and reason for the alert. CONCLUSION: During the 90-day study, implementation of a highly specific algorithm-based CDSS substantially improved prescribing quality with a high acceptance rate compared with previous studies.

[Assessment of the solid-liquid behavior of the liver for the diagnosis of diffuse disease using magnetic resonance elastography]. / Untersuchung des Fest-flüssig-Materialverhaltens der Leber zur nicht invasiven Diagnose diffuser Lebererkrankungen mittels Magnetresonanz-Elastografie.

PURPOSE: Recent magnetic resonance elastography (MRE) studies have reported the potential of this noninvasive method for diagnosing hepatic fibrosis based on the elastic properties of liver tissue. However, in many cases biological tissue responds to mechanical vibrations as a combined solid-liquid body causing MRE-derived elastic parameters to become functions of the applied vibration frequency. Therefore a multi-frequency MRE study of liver was performed and the potential of the method for separating healthy from fibrotic liver was investigated. The aim of this study was the increase of the accuracy of liver elastography by analyzing multi-frequency MRE examinations using the springpot model. MATERIALS AND METHODS: 18 healthy volunteers and 10 patients were examined by multi-frequency MRE of the liver in a frequency range between 25 Hz and 62.5 Hz. The liver was mechanically excited with four harmonic vibrations simultaneously. The measured dispersion of the complex modulus was analyzed using the springpot model which accounts for both elastic and viscous properties of a material with 2 independent parameters. RESULTS: The mechanical stimulation and the motion encoding according to the multi-frequency approach was implemented successfully. Significant differences (p < 0.05) were found in the hepatic viscoelasticities of normal livers. The separation of healthy volunteers and patients was achieved with a sensitivity and specificity of 80 and 100 %, respectively. CONCLUSION: Using the springpot model, multi-frequency MRE is sensitive to interindividual differences in the hepatic viscoelastic properties of healthy volunteers. The obtained accuracy of the technique in separating healthy from fibrotic livers opens the possibility of applying multi-frequency MRE as a noninvasive method for diagnosing liver fibrosis in the future.

Algebraic Helmholtz inversion in planar magnetic resonance elastography.

Magnetic resonance elastography (MRE) is an increasingly used noninvasive modality for diagnosing diseases using the response of soft tissue to harmonic shear waves. We present a study on the algebraic Helmholtz inversion (AHI) applied to planar MRE, demonstrating that the deduced phase speed of shear waves depends strongly on the relative orientations of actuator polarization, motion encoding direction and image plane as well as on the actuator plate size, signal-to-noise ratio and discretization of the wave image. Results from the numerical calculation of harmonic elastic waves due to different excitation directions and simulated plate sizes are compared to experiments on a gel phantom. The results suggest that correct phase speed can be obtained despite these largely uncontrollable influences, if AHI is based on out-of-plane displacements and the actuator is driven at an optimal frequency yielding an optimal pixel per wavelength resolution in the wave image. Assuming plane waves, the required number of pixels per wavelength depends only on the degree of noise.

Calcium balance during calcitriol and paricalcitol administration in healthy humans.

OBJECTIVE: Secondary hyperparathyroidism in hemodialysis patients requires optimal correction of vitamin D deficiency with active vitamin D and analogues. It has been postulated that new vitamin D analogues, i.e. paricalcitol, efficiently suppress parathyroid hormone serum levels (PTH), but do not increase intestinal calcium absorption as much as calcitriol. The effects of calcitriol and paricalcitol on calcium balance can best be characterized under standardized conditions in healthy individuals with normal renal function, because the urinary calcium excretion at steady state corresponds to the net calcium absorption in the gut. METHODS: In a randomized, double-blind, placebo-controlled, 3-way crossover Phase I study in 13 healthy individuals we investigated the changes compared to placebo in PTH and urinary calcium excretion during 6-day treatment periods with paricalcitol (1.5 microg/day) and calcitriol (0.5 microg/day). RESULTS: 24-hour urinary calcium excretion was stable during 6 days of placebo administration. Neither paricalcitol nor calcitriol significantly changed calcium excretion. Urinary creatinine, magnesium and phosphate excretion also remained unchanged over the study periods irrespective of the treatment. However, calcitriol was shown to be effective in reducing iPTH levels during 6 days of treatment (mean reduction 4.03+/-0.69 pmol/l), whereas paricalcitol had no effect. CONCLUSION: Using a dosing ratio of 1:3 for calcitriol:paricalcitol, i.e. the same conversion factor used previously in studies on hemodialysis patients, only calcitriol was able to reduce iPTH levels in healthy individuals. Low-dose calcitriol reduced iPTH levels without raising calcium absorption and without including any hypercalcemia.

[Ethical and legal aspects of including patients unable to consent in acute therapy studies. Example of a medication study for the treatment of intracerebral hemorrhage--the Heidelberg procedure]. / Ethische und juristische Aspekte beim Einschluss nicht einwilligungsfähiger Patienten in Akuttherapie-Studien. Beispiel einer Arzneimittelstudie zur Behandlung intrazerebraler Blutungen--das Heidelberger Verfahren.

Clinical trials in patients who cannot sign an informed consent are only possible under certain circumstances. The present paper explains the legal prerequisites and ethic rationales, which may allow including patients in such a trial without having signed informed consent. Translation of these prerequisites into practice needs the implementation of special inclusion procedures. These procedures will be explained using the example of the recombinant factor VIIa (rFVIIa) trials for intracerebral hemorrhage.

Rule-based standardised switching of drugs at the interface between primary and tertiary care.

INTRODUCTION: Changes in drug treatment are frequently mandatory with hospital admission and discharge because hospital drug formularies are generally restricted to about 3000 drugs as compared to the many times this number - 62,000 in Germany - that are commercially available. Without computerised support, the process involved with switching drugs to a corresponding generic or a therapeutic equivalent is time-consuming and error-prone. METHODS: We have developed and tested a standardised interchange algorithm for subsequent implementation into a computerised decision support system that switches drugs to the corresponding generic or a therapeutic equivalent if they are not listed on the hospital drug formulary. RESULTS: The algorithm was retrospectively applied to the medication regimens of 120 patients (774 prescribed drugs containing 886 active ingredients) at their time of admission to surgical wards. Of the prescribed drugs, 52.8% (409/774) were part of the hospital drug formulary, thereby rendering a switch unnecessary. The 365 drugs not listed consisted of 392 active ingredients that were successfully switched to a corresponding generic (84.7%) or a therapeutic equivalent (10.2%). No specific switching procedures were defined for only 2.3% (20/886) of the active ingredients. In these cases, the drugs were either discontinued (4/20) or special drug classes, current diseases or co-medication required manual switching (8/20), or the drugs were continued unchanged and ordered from a wholesaler (8/20). CONCLUSION: Using a standardised interchange algorithm, pre-admission drug regimens can successfully be switched to drugs on a hospital drug formulary. These findings suggest that a computerised decision support system will likely be useful to support this important practice.

Reduction in non-glomerular renal clearance of the caffeine metabolite 1-methylxanthine by probenecid.

OBJECTIVE: Urinary caffeine metabolic ratios used to quantify the activity of numerous drug-metabolizing enzymes are an established component of cocktail approaches for metabolic phenotyping. Because in vitro evidence suggests that 1-methylxanthine (1-MX), a major caffeine metabolite, is actively secreted into urine by organic anion transporters (hOATs), coadministration of renal hOAT inhibitors like probenecid may impair these procedures. METHODS: In a randomized, placebo-controlled, double-blind crossover design, single oral doses of 300 mg caffeine with oral coadministration of placebo or 500 mg probenecid 3 times daily for 2 days were administered to 7 healthy men. The plasma and urine concentrations of caffeine and its major metabolites 1,7-dimethylxanthine (1,7-DMX) and 1-MX were determined by high-performance liquid chromatography. RESULTS: Coadministration of probenecid resulted in a 34% reduction of the renal clearance of 1-MX (mean +/- SD 190 +/- 42 versus 290 +/- 83 ml min(-1), 95% CI on difference 0.2, 200, p = 0.04) with a 41% reduction in its estimated non-glomerular clearance. The renal clearances of caffeine and 1,7-DMX and the area under the plasma concentration-time curves of all substances were not significantly changed. CONCLUSIONS: 1-MX undergoes renal tubular secretion which is substantially reduced by probenecid, possibly due to inhibition of renal hOATs. This inhibition may explain the influence of probenecid on urinary caffeine metabolic ratios and, thus, its impact on the assessment of enzyme activities. It also suggests that 1-MX might serve as a model substrate for the renal tubular transport of organic anions.

Horizontal shear wave scattering from a nonwelded interface observed by magnetic resonance elastography.

A method based on magnetic resonance elastography is presented that allows measuring the weldedness of interfaces between soft tissue layers. The technique exploits the dependence of shear wave scattering at elastic interfaces on the frequency of vibration. Experiments were performed on gel phantoms including differently welded interfaces. Plane wave excitation parallel to the planar interface with corresponding motion sensitization enabled the observation of only shear-horizontal (SH) wave scattering. Spatio-temporal filtering was applied to calculate scattering coefficients from the amplitudes of the incident, transmitted and reflected SH-waves in the vicinity of the interface. The results illustrate that acoustic wave scattering in soft tissues is largely dependent on the connectivity of interfaces, which is potentially interesting for imaging tissue mechanics in medicine and biology.