Dynamic prediction of mortality in COVID-19 patients in the intensive care unit: A retrospective multi-center cohort study.

Background: The COVID-19 pandemic continues to overwhelm intensive care units (ICUs) worldwide, and improved prediction of mortality among COVID-19 patients could assist decision making in the ICU setting. In this work, we report on the development and validation of a dynamic mortality model specifically for critically ill COVID-19 patients and discuss its potential utility in the ICU. Methods: We collected electronic medical record (EMR) data from 3222 ICU admissions with a COVID-19 infection from 25 different ICUs in the Netherlands. We extracted daily observations of each patient and fitted both a linear (logistic regression) and non-linear (random forest) model to predict mortality within 24 h from the moment of prediction. Isotonic regression was used to re-calibrate the predictions of the fitted models. We evaluated the models in a leave-one-ICU-out (LOIO) cross-validation procedure. Results: The logistic regression and random forest model yielded an area under the receiver operating characteristic curve of 0.87 [0.85; 0.88] and 0.86 [0.84; 0.88], respectively. The recalibrated model predictions showed a calibration intercept of -0.04 [-0.12; 0.04] and slope of 0.90 [0.85; 0.95] for logistic regression model and a calibration intercept of -0.19 [-0.27; -0.10] and slope of 0.89 [0.84; 0.94] for the random forest model. Discussion: We presented a model for dynamic mortality prediction, specifically for critically ill COVID-19 patients, which predicts near-term mortality rather than in-ICU mortality. The potential clinical utility of dynamic mortality models such as benchmarking, improving resource allocation and informing family members, as well as the development of models with more causal structure, should be topics for future research.

New Twists of 3D Chiral Metamaterials.

Rationally designed artificial materials, called metamaterials, allow for tailoring effective material properties beyond ("meta") the properties of their bulk ingredient materials. This statement is especially true for chiral metamaterials, as unlocking certain degrees of freedom necessarily requires broken centrosymmetry. While the field of chiral electromagnetic/optical metamaterials has become rather mature, the field of elastic/mechanical metamaterials is just emerging and wide open. This research news reviews recent theoretical and experimental progress concerning 3D chiral mechanical and optical metamaterials, with special emphasis on work performed at KIT.

[A pregnant patient with spontaneous haemothorax: hereditary haemorrhagic telangiectasia in pregnancy]. / Een zwangere met een spontane hematothorax.

BACKGROUND: The incidence of hereditary haemorrhagic telangiectasia (HHT - Osler-Weber-Rendu disease) in the Netherlands is 1:5000 but approximately 1:1300 in people from the Antilles. The disease is characterised by the development of telangiectasia and arteriovenous malformations (AVMs) that may result in serious morbidity and mortality. CASE DESCRIPTION: A 31-year-old primigravid patient consulted her general practitioner at 31 1/7 weeks gestational age with dyspnoea. She was referred for further diagnostics because of suspected pulmonary embolism. A CT scan showed haemothorax and a bleeding arteriovenous malformation (AVM) in the left lung. Family history suggested the possibility of HHT. After multidisciplinary consideration, a primary caesarean section was performed, followed by embolisation of the AVM during the same surgical session. The patient had a gene mutation consistent with HHT type 2. CONCLUSION: Pregnant patients with HHT are at risk of serious morbidity, especially if they are not screened for AVMs. A multidisciplinary approach for such patients, with consideration of various scenarios, is highly recommended.

Monitoring of small laboratory animal experiments by a designated web-based database.

Multiple-parametric small animal experiments require, by their very nature, a sufficient number of animals which may need to be large to obtain statistically significant results.(1) For this reason database-related systems are required to collect the experimental data as well as to support the later (re-) analysis of the information gained during the experiments. In particular, the monitoring of animal welfare is simplified by the inclusion of warning signals (for instance, loss in body weight >20%). Digital patient charts have been developed for human patients but are usually not able to fulfill the specific needs of animal experimentation. To address this problem a unique web-based monitoring system using standard MySQL, PHP, and nginx has been created. PHP was used to create the HTML-based user interface and outputs in a variety of proprietary file formats, namely portable document format (PDF) or spreadsheet files. This article demonstrates its fundamental features and the easy and secure access it offers to the data from any place using a web browser. This information will help other researchers create their own individual databases in a similar way. The use of QR-codes plays an important role for stress-free use of the database. We demonstrate a way to easily identify all animals and samples and data collected during the experiments. Specific ways to record animal irradiations and chemotherapy applications are shown. This new analysis tool allows the effective and detailed analysis of huge amounts of data collected through small animal experiments. It supports proper statistical evaluation of the data and provides excellent retrievable data storage.

Motion artifact reducing reconstruction of 4D CT image data for the analysis of respiratory dynamics.

OBJECTIVES: Respiratory motion represents a major problem in radiotherapy of thoracic and abdominal tumors. Methods for compensation require comprehensive knowledge of underlying dynamics. Therefore, 4D (= 3D + t) CT data can be helpful. But modern CT scanners cannot scan a large region of interest simultaneously. So patients have to be scanned in segments. Commonly used approaches for reconstructing the data segments into 4D CT images cause motion artifacts. In order to reduce the artifacts, a new method for 4D CT reconstruction is presented. The resulting data sets are used to analyze respiratory motion. METHODS: Spatiotemporal CT image sequences of lung cancer patients were acquired using a multi-slice CT in cine mode during free breathing. 4D CT reconstruction was done by optical flow based temporal interpolation. The resulting 4D image data were compared with data generated by the commonly used nearest neighbor reconstruction. Subsequent motion analysis is mainly concerned with tumor mobility. RESULTS: The presented optical flow-based method enables the reconstruction of 3D CT images at arbitrarily chosen points of the patient's breathing cycle. A considerable reduction of motion artifacts has been proven in eight patient data sets. Motion analysis showed that tumor mobility differs strongly between the patients. CONCLUSIONS: Due to the proved reduction of motion artifacts, the optical flow-based 4D CT reconstruction offers the possibility of high-quality motion analysis. Because the method is based on an interpolation scheme, it additionally has the potential to enable the reconstruction of 4D CT data from a lesser number of scans.

Pharmacokinetics of Gadomer-17, a new dendritic magnetic resonance contrast agent.

RATIONALE AND OBJECTIVES: Gadomer-17 is a new magnetic resonance (MR) contrast medium presently in clinical development. It is a dendritic gadolinium (Gd) chelate carrying 24 Gd ions. This study investigated the pharmacokinetic behavior of this contrast medium. METHODS: The pharmacokinetics of Gadomer-17 were investigated in different species (rat, rabbit, dog, monkey) for up to 7 days after intravenous (i.v.) injection of 25-100 micromol/kg body weight. In addition, elimination and biodistribution were evaluated after single i.v. injection of Gadomer-17 in rats. RESULTS: After i.v. injection Gadomer-17 distributes almost exclusively within the intravascular space without significant diffusion into the interstitial space. The volume of distribution (Vc) in the initial or alpha-phase ranged from 0.04 l/kg (rats, rabbits) to 0.06 l/kg (monkeys) and 0.07 l/kg (dogs), which reflects mainly the plasma volume. The blood/plasma concentration profile was found to be biphasic. The volume of distribution at a steady state is clearly smaller than that of other contrast media, which distribute to the extracellular space. After single i.v. injection in rats, the dendritic contrast medium was rapidly and completely eliminated from the body, mainly via glomerular filtration. No long-term accumulation or retention of the nonmetabolized agent was detectable in organs or tissues. CONCLUSIONS: Gadomer-17 is a promising new MR contrast medium that has an intravascular distribution and a rapid renal elimination.

Rapid multimethod for verification and determination of toxic pesticides in whole blood by means of capillary GC-MS.

A rapid and single multimethod was developed to determine substances of different pesticide classes in whole blood in the event of acute human intoxications, as required by EU Commission Directive 96/46. The method was validated by an in-house and an independent laboratory validation. Whole blood is hemolyzed and then deproteinized. After extraction of the supernatant, blood levels are determined by gas chromatography-mass spectrometry. The method, which can be performed within 120 min, covers 15 active substances (8 organophosphate pesticides, 2 carbamates, 3 pyrethroids, 1 azole, and 1 organochlorine pesticide) classified as toxic or very toxic. These compounds can be identified down to concentrations between 100 and 1000 ng/mL by comparison of their mass spectra to those in a commercial pesticide mass spectra library. Using the standard addition method, they can be quantitated down to concentrations between 30 and 200 ng/mL. These limits of quantitation are considered to be sufficient in comparison to respective LD50 values.

Gadopentetate dimeglumine excretion into human breast milk during lactation.

PURPOSE: To analyze the amount of gadopentetate dimeglumine excreted into human breast milk following intravenous injection of a clinical dose. MATERIALS AND METHODS: Gadopentetate dimeglumine was injected intravenously in 20 lactating women (23-38 years of age). Breast-feeding was interrupted for at least 24 hours. Serial samples of expressed milk were collected and analyzed for gadolinium concentration by means of inductively coupled plasma atomic emission spectrometry at a wavelength of 342.247 nm. RESULTS: The cumulative amount of gadolinium excreted in human breast milk during 24 hours was 0.57 micromol +/- 0.71 (SD; range, 0.05-3.0 micromol). The excreted dose was thus less than 0.04% of the administered intravenous dose (range, 0.001%-0.04%; mean, 0.009% +/- 0.010) for all cases. CONCLUSION: Less than 0.04% of administered gadopentetate dimeglumine is excreted into human breast milk. The amount transferred to a nursing infant orally would be far more than 100 times less than the permitted intravenous dose (200 micromol per kilogram of body weight) for neonates. The recommendation of a 24-hour suspension of breast-feeding for lactating women should thus be reconsidered.

Is absolute noninvasive temperature measurement by the Pr[MOE-DO3A] complex feasible.

Recently, the feasibility of the praseodymium complex of 10-(2-methoxyethyl)-1,4,7,10-tetraaza-cyclododecane-1,4,7-tr iacetate (Pr[MOE-DO3A]) for non-invasive temperature measurement via 1H spectroscopy has been demonstrated. Particularly the suitability of the complex for non-invasive temperature measurements including in vivo spectroscopy without spatial resolution as well as first spectroscopic imaging measurements at low temporal resolution (> or = 4 min) and high temporal resolution (breath hold, approximately 20 s) has been shown. As of today, calibration curves according to the particular experimental conditions are necessary. This work aims to clarify whether the Pr[MOE-DO3A] probe in conjunction with 1H-NMR spectroscopy allows non-invasive absolute temperature measurements with high accuracy. The measurement results from two different representative media, distilled water and human plasma, show a slight but significant dependence of the calibration curves on the surrounding medium. Calibration curves in water and plasma were derived for the temperature dependence of the chemical shift difference (F) between Pr[MOE-DO3A]'s OCH3 and water with F = -(27.53 +/- 0.04) + (0.125 +/- 0.001) x T and F = -(27.61 +/- 0.02) + (0.129 +/- 0.001) x T, respectively, with F in ppm and T in degrees C. However, the differences are minuscule even for the highest spectral resolution of 0.001 ppm/pt, so that they are indistinguishable under practical conditions. The estimated temperature errors are +/- 0.18 degrees C for water and +/- 0.14 degrees C for plasma and with that only slightly worse than the measurement accuracy of the fiber-optical temperature probe (+/- 0.1 degrees C). It can be concluded that the results obtained indicate the feasibility of the 1H spectroscopy method in conjunction with the Pr[MOE-DO3A] probe for absolute temperature measurements, with a maximum accuracy of +/- 0.2 degrees C.

Non-invasive MR thermometry by 2D spectroscopic imaging of the Pr[MOE-DO3A] complex.

Future progress in regional hyperthermia requires a practical method for non-invasive thermometry. In magnetic resonance tomography, spin density, T1 relaxation time, diffusion coefficient and proton resonance frequency are candidates to measure temperature distributions. When used clinically in the pelvic region, all these methods are compromized by artifacts arising from different tissues, tissue alterations under hyperthermia, physiological and random movements, inhomogeneities, drift phenomena, and field instabilities. In this study a paramagnetic complex was evaluated, Pr[MOE-DO3A], with praseodymium as central atom, similar to common gadolinium containing MRI contrast media. The temperature dependence of its methoxy side group approximately -24 ppm downfield from the water resonance at 25 degrees C was employed to determine 2-D temperature distributions in a cylindrical agar phantom containing 9.5 mM of Pr[MOE-DO3A]. The phantom was heated externally through a water jacket creating a stationary temperature distribution throughout the phantom. At first, the correlation between temperature and the chemical shift of the methyl group of the lanthanide complex Pr[MOE-DO3A] was determined. Calibration curves obtained exhibited a linear relationship of 0.12 +/- 0.01 ppm/degree C, nearly independent from the surrounding medium. Local temperature distributions were determined employing the spatially resolved method of spectroscopic imaging (SI). 2-D spectroscopic images for three orthogonal slices were obtained by narrow-band excitation and 16 phase encoding steps in two dimensions. The FOV was 180 mm and the slice thickness in all cases was 20 mm for maximal spatial temperature resolution (11.2 x 11.2 mm2). The results indicate a measurement time of about 5s per acquisition under the following conditions: An estimated concentration of 1 mmol/l, a reduced matrix size of 8 x 8, and a reduced repetition time of 3 x T1 (TR approximately 85 ms). Those SI measurements produced a SNR of approximately 4 per acquisition, a measurements duration of 10-20 s, equivalent to two to four acquisitions per spectrum, seem sufficient for online temperature monitoring during hyperthermia. The in vitro data suggest the spectroscopic temperature measurement utilizing a temperature-sensitive Pr[MOE-DO3A] complex with a therapeutically realistic concentration of 1 mmol/l to be suitable for clinical use. Compared to the methods tested so far (rho, T1, diffusion, proton resonance), the method presented has the unique advantage of being less susceptible to artifacts. The competing methods of non-invasive thermometry employing magnetic resonance imaging are currently being investigated using the same experimental setup.

Magnetic iron oxide particles coated with carboxydextran for parenteral administration and liver contrasting. Pre-clinical profile of SH U555A.

RATIONALE AND OBJECTIVES: To evaluate the physical and pharmacological profiles of SH U555A, a suspension of magnetic iron oxide particles that is designed to enhance the visualization of liver tumors and metastases. MATERIAL AND METHODS: Chemical and physical methods were used to characterize the size and structure of these magnetic iron oxide particles in aqueous solution. The biodistribution and pharmacokinetics of the particles were studied in mice, rats and dogs. The imaging efficacy of the particles was demonstrated by MR imaging in rat liver tumors RESULTS: The SH U555A particles consist of low-molecular-weight carboxydextran-coated iron oxides predominantly of the gamma-Fe2O3 form with a hydrodynamic diameter ranging from 57-59 nm and strong T2 relaxivity of 164 liters x mmol(-1) x s(-1) (water, 0.47 T). In rats the particles exhibited a dose-dependent half-life of between 2 and 3 days in the liver at a dose of 20 micromol Fe/kg and a shorter half-life at lower doses. No major side effects were found. In a rat tumor model the tumor-to-liver contrast was markedly improved after i.v. administration of SH U555A. At a dose of 14 micromol Fe/kg the half-maximal contrast-effect was obtained even in nonoptimized T1-weighted spin-echo images. CONCLUSION: SH U555A is a superparamagnetic MR contrast agent for i.v. administration and has substantial potential for the demarcation of liver tumors.

[Thermometry by measuring the chemical shift of lanthanide complex]. / Thermometrie durch Messung der chemischen Verschiebung eines Lanthanidenkomplexes.

BACKGROUND: In the long-term, non-invasive thermometry is vital for the continued clinical and technological development of regional hyperthermia. In magnetic resonance tomography. T1 relaxation time, diffusion and proton resonance frequency are used to measure temperature distributions. When used clinically in the pelvic region, all of these methods are plagued with errors and artefacts on account of the tissue relationships, tissue changes under hyperthermia, physiological and stochastic movements, inhomogeneities, drift phenomena and instabilities. MATERIAL AND METHOD: We tested the relationship between the temperature and the chemical shift of a methyl group of a lanthanide complex with central atom praseodymium (Pr-MOE-DO3A. Schering AG). To do this we used cylindrical phantoms containing a 5-mmol-solution of this temperature-sensitive substance. High resolution spectra and relaxation times were determined in a Bruker AMX at 11.5 T. A calibration curve was then recorded by a Siemens Magnetom SP63 at 1.5 T. Local temperature distributions were determined using the chemical shift imaging method, with a matrix size of 16 x 8 and a narrow-band excitation pulse. The temperature distribution was created using a Nd:YAG laser applicator. RESULTS: At a distance of -25.7 ppm from the water line, we found a singlet line with a temperature-dependent chemical shift of 0.13 ppm/C. In the phantom experiment we found that the chemical shift had a linear relationship with a gradient independent of the surroundings, and a temperature resolution of +/-0.6 degree C. With a concentration of 1 mmol/l, a matrix size of 8 x 8 and a measurement period of 5 s per acquisition, phantom measurements using the CSI method produced a signal to noise ratio of 3.5 per acquisition, i.e a measurement period of 10 to 20 s per spectrum. CONCLUSIONS: Our in vitro data show that spectroscopic temperature measurement using a temperature-sensitive praseodymium complex with a therapeutically practical concentration of 1 mmol/l already appears to be suitable for clinical use Compared with the methods tested so far (T1, diffusion, proton resonance), this method has the special advantage of not being very susceptible to artefacts. The competing methods of non-invasive thermometry using magnetic resonance tomography/spectroscopy will be investigated next.

Noninvasive temperature measurement in vivo using a temperature-sensitive lanthanide complex and 1H magnetic resonance spectroscopy.

A new lanthanide complex, praseodymium-2-methoxyethyl-DO3A, was tested as a temperature indicator for 1H magnetic resonance spectroscopy under in vivo conditions, using a 2-T imaging system. The chemical shift of the methoxy group of the compound is strongly temperature dependent. In vitro, a shift change of -0.131 ppm/degree C was found. The signal was shifted by about -24 ppm relative to the water signal, allowing easy water suppression and signal identification in vivo. The body temperatures of eight anesthetized rats were measured in the liver after intravenous administration of 1 mmol/kg of the praseodymium complex under different heating conditions of the animal. The temperatures calculated from the spectra were in good agreement (deviation < +/- 1 degree C) with values obtained simultaneously with a thermocouple placed in the rectum of the animals.

Pre-clinical evaluation of gadobutrol: a new, neutral, extracellular contrast agent for magnetic resonance imaging.

The Gd(3+)-complex of 10-(2,3-dihydroxy-1-hydroxymethylpropyl)-1,4,7,10-tetraazacyclo dodecane-1,4,7-triacetic acid(gadobutrol) is a new, neutral Gd-chelate for use as an extracellular contrast agent in magnetic resonance imaging (MRI). The blood level in dogs after intravenous (i.v.) injection decreased with a terminal half-life of about 45 min, the clearance was about 3.75 ml/min per kg and the distribution volume of 0.23 l/kg suggested an extracellular distribution. Biodistribution experiments in rats revealed that only a very small amount (0.16%) of the dose was left in the body 7 days after i.v. injection. Measurable amounts of Gd could be detected only in the liver, kidneys and bones. The osmolality (0.57 osmol/kg at 0.5 mol/l and 1.39 osmol/kg at 1 mol/l) is in the range of other low osmolality contrast media for MRI. Only very little interaction with biologically relevant molecules was suggested by a histamine release test and a lysozyme inhibition test. An i.v.-LD50 of 23 mmol/kg in mice combined with a comparatively high T1-relaxivity (5.6 l/mmol per s at 0.47 T and 6.1 l/mmol per s at 2 T) in plasma promises a high margin of safety. In preliminary imaging experiments, gadobutrol caused high enhancement in different lesions (cerebral infarct, brain tumor) of the rat. Tripling of the typical clinical dose of 0.1 mmol/kg was shown to provide additional diagnostic gain in lesions of this type.

Phase I clinical evaluation of Gd-EOB-DTPA as a hepatobiliary MR contrast agent: safety, pharmacokinetics, and MR imaging.

PURPOSE: To determine the safety, pharmacokinetics, and magnetic resonance (MR) imaging results of gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA) as a contrast agent for use in hepatobiliary MR imaging. MATERIALS AND METHODS: Gd-EOB-DTPA was tested at doses of 10, 25, 50, and 100 mumol per kilogram of body weight. Results of laboratory tests, clinical measurements, and pharmacokinetic data were obtained in 44 healthy volunteers in a double-blind, randomized, placebo-controlled design. MR images were obtained in another 16 healthy volunteers before and up to 6 hours after fast intravenous administration of Gd-EOB-DTPA. RESULTS: Gd-EOB-DTPA was well tolerated, with no important side effects or changes in laboratory parameters. Homogeneous enhancement of liver parenchyma was observed immediately after injection of the contrast agent. Peak liver signal intensity was noted 20 minutes after injection, followed by plateaulike enhancement over about 2 hours. The common bile duct was hyperintense within 10 minutes after injection in all volunteers. CONCLUSION: Gd-EOB-DTPA is safe and efficient for MR imaging of the liver.

Comparison of iopamidol and ioversol in vitro and in animal studies.

In the present series of studies we investigated differences in vitro and in animal experiments between iopamidol (Iopamiron, CAS 60166-93-0) and ioversol (CAS 87771-40-2). The studies included the in vitro investigations partition coefficient, lysozyme inhibition, coagulation time and erythrocyte morphology as well as the in vivo paradigms acute toxicity, neural toxicity, general behavior/locomotor activity and angiography. Iopamidol was superior to ioversol in most of the tests. In spite of its higher hydrophilicity, ioversol did not show improved tolerance in comparison to iopamidol.

Characterization of a gadolinium-labeled cholesterol derivative as an organ-specific contrast agent for adrenal MR imaging.

The purpose of the study was to determine if derivatization of cholesterol with a paramagnetic label could result in an organ-specific contrast agent for magnetic resonance imaging of the adrenal glands. Gadolinium-DO3A-labeled cholesterol was synthesized and the relaxivities in water and blood plasma determined at 0.47 T and 40 degrees C. Organ distribution was measured at 2 (n = 2) and 24 (n = 2) hours after intravenous injection of a 50 mumol/kg dose of Gd-DO3A-cholesterol in rats weighing 220-240 g. T1-weighted spin-echo images were acquired at 2 T before and after injection of 50 mumol/kg Gd-DO3A-cholesterol (n = 2) and Gd-DTPA (diethylenetriaminepentaacetic acid)-albumin (n = 2). More than 99% of the Gd-DO3A-cholesterol was found to be protein bound in bovine serum. High T1 and T2 relaxivities were found in water and plasma. High tissue concentrations of Gd-DO3A-cholesterol were found only in adrenal glands and liver. At 24 hours, adrenal gadolinium concentrations were about 10 times higher than in blood. At 2 hours after injection of Gd-DO3A-cholesterol, enhancement was 162% in adrenal glands and 146% in liver. With Gd-DTPA-albumin, enhancement values were 57% and 56%, respectively.