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.

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.

[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.

Pharmacokinetics, dose proportionality, and tolerability of gadobutrol after single intravenous injection in healthy volunteers.

RATIONALE AND OBJECTIVES: Gadobutrol is a new gadolinium-based hydrophilic and neutral macrocyclic contrast medium for magnetic resonance imaging. In this article, the authors report on the first application of gadobutrol in humans, up to a dose of 0.5 mmol/kg. METHODS: Gadobutrol was investigated after single intravenous administration in two phase-1 studies testing low (0.5 mol/L) and high concentrations (1 mol/L) in healthy, male volunteers using a double-blind, randomized, placebo-controlled study with n = 55 for the low concentration (0.04, 0.1, 0.2, 0.3, and 0.4 mmol/kg body weight), followed by n = 36 for the high concentration (0.3, 0.4, and 0.5 mmol/kg body weight). Vital signs and laboratory parameters were measured for all dose groups investigated, whereas for the calculation of the pharmacokinetic parameters, the dose groups 0.04, 0.1, and 0.4 mmol/kg body weight were selected. RESULTS: Gadobutrol was well tolerated up to doses of 0.5 mmol/kg, and no relevant changes in vital signs and laboratory parameters occurred. The terminal disposition half-life of gadobutrol in plasma was approximately 1.5 hours. Total clearance approximated renal clearance and approximated the value of 120 mL/min, indicating glomerular filtration as the main pathway of elimination. The steady-state volume of distribution indicated predominantly extracellular distribution of gadobutrol. No metabolites were detected. The renal excretion rate was linear over the large dose range tested, indicating dose-proportionate, first-order kinetics of gadobutrol. CONCLUSION: Single intravenous administration of gadobutrol was well tolerated up to the dose level of 0.5 mmol/kg body weight. These factors suggest that gadobutrol will be a safe magnetic resonance imaging contrast agent.

In vivo and in vitro evaluation of Gd-DTPA-polylysine as a macromolecular contrast agent for magnetic resonance imaging.

Polylysine covalently linked to moieties of gadopentetate (Gd-DTPA), for use as a macromolecular blood pool marker for contrast material-enhanced magnetic resonance imaging (MRI), was characterized by means of physicochemical measurements and pharmacokinetics in rats and rabbits and compared with Gd-DTPA. Gd-DTPA-polylysine was composed of a series of polymers of different molecular sizes that on average were labeled with 60 to 70 Gd-DTPA moieties (average molecular weight, 48,700 daltons [D]). For the macromolecular compound Gd-DTPA-polylysine, relaxivity was three times higher than that of Gd-DTPA. The LD50 value of 17 mmol/kg reflects a fairly high acute intravenous tolerance of the macromolecular compound in mice. Even though the volume of distribution of Gd-DTPA-polylysine in rabbits approached the extracellular fluid space (indicating that the macromolecular compound was also leaking slowly into the interstitial space), the half-life of distribution of the macromolecular compound in the extracellular fluid space was significantly prolonged, thus making the compound suitable as a blood pool marker for MRI. In rats the elimination of Gd-DTPA-polylysine occurred predominantly via the renal route. High-pressure liquid chromatography-size-exclusion chromatography of the fractionated urine samples revealed that the renal clearance must be the integral sum of the separate clearances of each molecular weight species. No biodegradation of the polypeptide was observed, and biodistribution studies revealed only minimal retention of Gd in the body of the rat.

Pharmaceutical properties, biodistribution, and imaging characteristics of manganese-mesoporphyrin. A potential hepatobiliary contrast agent for magnetic resonance imaging.

OBJECTIVES: Manganese (III) mesoporphyrin (Mn-mesoporphyrin) was investigated for its pharmaceutical properties and magnetic resonance imaging characteristics as a potential hepatobiliary contrast agent. METHODS: Solubility, partition coefficient, plasma binding, proton relaxation enhancement, biodistribution, biliary excretion, liver extraction ratio, and liver enhancement were measured in various in-vitro and in-vivo systems. RESULTS: Mn-mesoporphyrin was soluble and stable at moderate alkaline pH in phosphate buffer. The octanol/water coefficient was 25.98, and the compound was highly protein bound. R1 for water and plasma were 1.94 and 2.35 L/mmol sec, respectively. R1 in liver was calculated to be 15.72 L/mmol sec. Biodistribution studies in rats and mice confirmed hepatotrophic properties and biliary excretion was 65% over 24 hours. First pass liver uptake was 15%. Magnetic resonance imaging studies showed persistent liver enhancement at 0.05 mmol/kg. CONCLUSION: Mn-mesoporphyrin is a lipophilic compound that shows potential as a hepatobiliary magnetic resonance contrast agent.

Biliary excretion and pharmacokinetics of a gadolinium chelate used as a liver-specific contrast agent for magnetic resonance imaging in the rat.

The introduction of a lipophilic moiety into the gadolinium chelate Gd-DTPA (dimeglumine gadopentetate, Magnevist) yielded Gd-EOB-DTPA (short form), which has potential as a magnetic resonance contrast agent for liver mass screening. The pharmacokinetics of Gd-EOB-DTPA in rats is nonlinear because after correction for the 10-fold difference in dose, the area under the curve of plasma concentration versus time from time zero to infinity after single intravenous application of two different doses were not superimposable, and the amounts excreted renally and extrarenally differed significantly. However, for both dose groups tested, the values of renal clearance (9.96 and 11.1 mL/min.kg, respectively) were close to the value of glomerular filtration in the rat. Michaelis-Menten kinetics in the extrarenal elimination was therefore considered as the rate-limiting process of Gd-EOB-DTPA, the binding to plasma protein of which is small (10.3 +/- 1.4%). Thus, biliary elimination was significantly inhibited by the intravenous coadministration of sulfobromophthalein (a decrease from 39.5 +/- 3.17 to 30.7 +/- 5.30% of the dose was observed from 0 to 90 min postinoculation under coadministration of the inhibitor), whereas tauroglycocholate revealed no effect, indicating the involvement of the so-called organic anion plasma membrane transport system for the hepatic uptake. The transport of Gd-EOB-DTPA from the cytoplasm to the bile is mainly determined by the capacity of the transport protein glutathione-S-transferase as demonstrated by in vitro binding studies. A hepatobiliary transport maximum of 9.2 mumol/min.kg was evaluated by infusion studies. No metabolites were detected either in the bile or in the urine, and enterohepatic circulation can be excluded.

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.

[Pelvimetry using magnetic resonance tomography]. / Pelvimetrie mittels Kernspintomographie.

20 woman were examined before and after partum by means of conventional and magnetic resonance pelvimetry. Besides the usual data regarding the morphology and diameters of the pelvis, MRI gives information on the soft tissues of the birth canal without the added risk of irradiation to the mother and foetus. As shown by studies done in the USA it is also possible to determine foetal maturity by MRI; this will be done in the future.

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.

Pharmacokinetics in rats, dogs and monkeys of a gadolinium chelate used as a liver-specific contrast agent for magnetic resonance imaging.

The introduction of the lipophilic moiety, ethoxybenzyl, into the gadolinium chelate dimeglumine gadopentetate (Gd-DTPA, Magnevist, CAS 86050-77-3) yielded (4S) 4-(4-ethoxybenzyl)-3,6,9-tris (carboxylatomethyl)-3,6,9-triazaundecandioic acid, gadolinium complex, disodium salt (Gd-EOB-DTPA), a compound with a potential as a magnetic resonance contrast agent for liver mass screening. Both in the rat and in the dog the pharmacokinetics of Gd-EOB-DTPA were nonlinear in the dose range of 0.05-0.5 mmol/kg (rat) and 0.03-0.25 mmol/kg (dog) since after correction for the difference in dose the plasma concentration-time profiles were not superimposable and the amounts excreted renally and fecally differed significantly (p < 0.05). Extrarenal elimination played an important role since fecal elimination (% of dose) was 73.4 +/- 5.6 in rats (0.05 mmol/kg), 70.1 +/- 4.0 in dogs (0.03 mmol/kg) and 32.1 +/- 6.4 in monkeys (0.25 mmol/kg). However, in all species investigated, the values of renal clearance (Clr) were independent of dose and close to the value of the glomerular filtration rate (Clr in ml/min.kg: 10.4 +/- 3.5 in rats; 3.88 +/- 0.8 in dogs; 1.01 +/- 0.3 in monkeys). Therefore, the pharmacokinetics of Gd-EOB-DTPA can best be described by a capacity-limited transport process via the biliary route of elimination thus strongly resembling the pharmacokinetics of some biliary X-ray contrast media (iotroxic, iodipamic or idoxamic acid) or the synthetic dyes (indocyanine green). However, contrary to the latter agents the plasma binding (%) of Gd-EOB-DTPA was low in all species (10.3 +/- 1.4 in rats: 10.0 +/- 1.3 in dogs; 17.5 +/- 1.0 in monkeys).

Preclinical testing of iopromide. 1st communication: pharmacological evaluation.

Pharmacological and pharmacokinetic characteristics of the non-ionic monomeric X-ray contrast agent iopromide (Ultravist, CAS 73334-07-3) were evaluated in preclinical studies. The scope of investigations included in vitro tests such as the determination of protein binding, the inhibition of complement, lysozyme, urokinase, platelet aggregation, the release of histamine, the influence on thromboplastin time. In vivo studies included bleeding time in rat, neural tolerance after intracisternal injection or administration into the carotid artery. Pharmacokinetic studies were performed in rats and dogs. Iopromide could be shown to be well tolerated in all the tests and species. Its pharmacokinetics was in agreement with the characteristics of an extracellular contrast agent with rapid renal elimination.

Formation of 2-methyltryptophan in the biosynthesis of thiostrepton: isolation of S-adenosylmethionine:tryptophan 2-methyltransferase.

L-2-Methyltryptophan was found to be an intermediate in the biosynthesis of the antibiotic thiostrepton. It was isolated from growing cultures and resting cells of Streptomyces laurentii in trapping experiments after the application of labeled L-methionine or L-tryptophan. Its formation from L-tryptophan and S-adenosylmethionine was studied in a cell-free extract of S. laurentii. Although several attempts to purify the soluble methyltransferase by standard methods failed, some of its characteristics could be determined in the crude extract. The enzyme has a sharp pH optimum at pH 7.8. The apparent Km value for S-adenosylmethionine is 120 microM and the Ki value for S-adenosylhomocysteine is 480 microM. The enzyme is not stereoselective with respect to D- or L-tryptophan, but the D-isomer is converted at a slower rate than the L-isomer. Indolepyruvic acid is also methylated, while indole is not a substrate. The methyl group is transferred with retention of its configuration, contrary to most other methyltransferase reactions.

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.