Blood Flow Velocity Pulsatility and Arterial Diameter Pulsatility Measurements of the Intracranial Arteries Using 4D PC-MRI.

4D phase contrast magnetic resonance imaging (PC-MRI) allows for the visualization and quantification of the cerebral blood flow. A drawback of software that is used to quantify the cerebral blood flow is that it oftentimes assumes a static arterial luminal area over the cardiac cycle. Quantifying the lumen area pulsatility index (aPI), i.e. the change in lumen area due to an increase in distending pressure over the cardiac cycle, can provide insight in the stiffness of the arteries. Arterial stiffness has received increased attention as a predictor in the development of cerebrovascular disease. In this study, we introduce software that allows for measurement of the aPI as well as the blood flow velocity pulsatility index (vPI) from 4D PC-MRI. The internal carotid arteries of seven volunteers were imaged using 7 T MRI. The aPI and vPI measurements from 4D PC-MRI were validated against measurements from 2D PC-MRI at two levels of the internal carotid arteries (C3 and C7). The aPI and vPI computed from 4D PC-MRI were comparable to those measured from 2D PC-MRI (aPI: mean difference: 0.03 (limits of agreement: -0.14 - 0.23); vPI: 0.03 (-0.17-0.23)). The measured blood flow rate for the C3 and C7 segments was similar, indicating that our proposed software correctly captures the variation in arterial lumen area and blood flow velocity that exists along the distal end of the carotid artery. Our software may potentially aid in identifying changes in arterial stiffness of the intracranial arteries caused by pathological changes to the vessel wall.

An anomaly detection approach to identify chronic brain infarcts on MRI.

The performance of current machine learning methods to detect heterogeneous pathology is limited by the quantity and quality of pathology in medical images. A possible solution is anomaly detection; an approach that can detect all abnormalities by learning how 'normal' tissue looks like. In this work, we propose an anomaly detection method using a neural network architecture for the detection of chronic brain infarcts on brain MR images. The neural network was trained to learn the visual appearance of normal appearing brains of 697 patients. We evaluated its performance on the detection of chronic brain infarcts in 225 patients, which were previously labeled. Our proposed method detected 374 chronic brain infarcts (68% of the total amount of brain infarcts) which represented 97.5% of the total infarct volume. Additionally, 26 new brain infarcts were identified that were originally missed by the radiologist during radiological reading. Our proposed method also detected white matter hyperintensities, anomalous calcifications, and imaging artefacts. This work shows that anomaly detection is a powerful approach for the detection of multiple brain abnormalities, and can potentially be used to improve the radiological workflow efficiency by guiding radiologists to brain anomalies which otherwise remain unnoticed.

Arterial Remodeling of the Intracranial Arteries in Patients With Hypertension and Controls: A Postmortem Study.

The intracranial arteries play a major role in cerebrovascular disease, but arterial remodeling due to hypertension has not been well described in humans. We aimed to quantify this remodeling for: the basilar artery, the vertebral, internal carotid, middle/anterior (inferior)/posterior cerebral, posterior communicating, and superior cerebellar arteries of the circle of Willis. Ex vivo circle of Willis specimens, selected from individuals with (n=24) and without (n=25) a history of hypertension, were imaged at 7T magnetic resonance imaging using a 3-dimensional gradient-echo sequence. Subsequently, histological analysis was performed. We validated the vessel wall thickness and area measurements from magnetic resonance imaging against histology. Next, we investigated potential differences in vessel wall thickness and area between both groups using both techniques. Finally, using histological analysis, we investigated potential differences in arterial wall stiffness and atherosclerotic plaque severity and load. All analyses were unadjusted. Magnetic resonance imaging and histology showed comparable vessel wall thickness (mean difference: 0.04 mm (limits of agreement:-0.12 to 0.19 mm) and area (0.43 mm2 [-0.97 to 1.8 mm2]) measurements. We observed no statistically significant differences in vessel wall thickness and area between both groups using either technique. Histological analysis showed early and advanced atherosclerotic plaques in almost all arteries for both groups. The arterial wall stiffness was significantly higher for the internal carotid artery in the hypertensive group. Concluding, we did not observe vessel wall thickening in the circle of Willis arteries in individuals with a history of hypertension using either technique. Using histological analysis, we observed a difference in vessel wall composition for the internal carotid artery.

Subvoxel vessel wall thickness measurements of the intracranial arteries using a convolutional neural network.

Vessel wall thickening of the intracranial arteries has been associated with cerebrovascular disease and atherosclerotic plaque development. Visualization of the vessel wall has been enabled by recent advancements in vessel wall MRI. However, quantifying early wall thickening from these MR images is difficult and prone to severe overestimation, because the voxel size of clinically used acquisitions exceeds the wall thickness of the intracranial arteries. In this study, we aimed for accurate and precise subvoxel vessel wall thickness measurements. A convolutional neural network was trained on MR images of 34 ex vivo circle of Willis specimens, acquired with a clinically used protocol (isotropic acquired voxel size: 0.8 mm). Ground truth measurements were performed on images acquired with an ultra-high-resolution protocol (isotropic acquired voxel size: 0.11 mm) and were used for evaluation. Additionally, we determined the robustness of our method by applying Monte Carlo dropout and test time augmentation. Lastly, we applied our method on in vivo images of three intracranial aneurysms to measure their wall thickness. Our method shows resolvability of different vessel wall thicknesses, well below the acquired voxel size. The method described may facilitate quantitative measurements on MRI data for a wider range of clinical applications.

The Bacterial Gut Microbiota of Adult Patients Infected, Colonized or Noncolonized by Clostridioides difficile.

: Gut microbiota composition in patients with Clostridioides difficile colonization is not well investigated. We aimed to identify bacterial signatures associated with resistance and susceptibility to C. difficile colonization (CDC) and infection (CDI). Therefore, gut microbiota composition from patients with CDC (n = 41), with CDI (n = 41), and without CDC (controls, n = 43) was determined through 16S rRNA gene amplicon sequencing. Bacterial diversity was decreased in CDC and CDI patients (p<0.01). Overall microbiota composition was significantly different between control, CDC, and CDI patients (p = 0.001). Relative abundance of Clostridioides (most likely C. difficile) increased stepwise from controls to CDC and CDI patients. In addition, differential abundance analysis revealed that CDI patients' gut microbiota was characterized by significantly higher relative abundance of Bacteroides and Veillonella than CDC patients and controls. Control patients had significantly higher Eubacterium hallii and Fusicatenibacter abundance than colonized patients. Network analysis indicated that Fusicatenibacter was negatively associated with Clostridioides in CDI patients, while Veillonella was positively associated with Clostridioides in CDC patients. Bacterial microbiota diversity decreased in both CDC and CDI patients, but harbored a distinct microbiota. Eubacterium hallii and Fusicatenibacter may indicate resistance against C. difficile colonization and subsequent infection, while Veillonella may indicate susceptibility to colonization and infection by C. difficile.

[Is the discipline associated with self-confidence in handling rational antibiotic prescription? : Results from the MR2 study in German hospitals]. / Ist die Fachrichtung assoziiert mit der Selbstsicherheit im Umgang mit rationaler Antibiotikaverordnung? : Ergebnisse der MR2-Studien an deutschen Kliniken.

BACKGROUND: Besides public awareness and specialist knowledge and training of physicians, their self-confidence plays a key role for clinical decision-making in the respective area. OBJECTIVE: This exploratory study investigated the influence of the discipline on differences in self-confidence in dealing with antibiotics and in the self-rated knowledge. METHODS: In 2015 the multi-institutional reconnaissance of practice with multiresistant bacteria (MR2) questionnaire containing items on antibiotic prescription and multiresistant pathogens was sent out to 1061 physicians working in departments for internal medicine, general surgery, gynecology and obstetrics and urology. In 2017 a similar MR2 survey was sent to 1268 specialist and assistant physicians in anesthesiology in Germany. Besides demographic data 4 items on self-confidence in the use of antibiotic treatment and 11 items concerning self-rated knowledge about rational antibiotic therapy and multiresistant pathogens were included in the present analysis. Logistic regression analysis, the χ2-test and the Kruskal-Wallis test were used for statistical analysis of the influence of the discipline on these items. RESULTS: The response rates were 43% (456 out of 1061) from the non-anesthetists and 56% (705 out of 1268) from the anesthetists. Of the non-anesthetists 44% and 57% of the anesthetists had had no advanced training on antibiotic stewardship during the year before the study. In the overall analysis anesthetists (mean±SD: 2.53±0.54) were significantly less self-confident about antibiotics than colleagues from other departments (internal medicine: 3.10±0.50, general surgery: 2.97±0.44, gynecology and obstetrics: 3.12±0.42 and urology: 3.15±0.44) in the unadjusted (all p<0.001) and adjusted comparison. The analysis of self-rated knowledge about rational antibiotic prescription showed similar results. Senior consultant status and advanced training in infectiology were significantly associated with self-confidence and self-rated knowledge about antibiotics. CONCLUSION: Anesthetists showed significantly less self-confidence in dealing with antibiotics than colleagues from other disciplines. Advanced training on a rational prescription of antibiotics was associated with a greater self-confidence, so that the implementation of compulsory courses on rational antibiotic stewardship in the respective residency curriculum needs to be considered.

Tigecycline in critically ill patients on continuous renal replacement therapy: a population pharmacokinetic study.

BACKGROUND: Tigecycline is a vital antibiotic treatment option for infections caused by multiresistant bacteria in the intensive care unit (ICU). Acute kidney injury (AKI) is a common complication in the ICU requiring continuous renal replacement therapy (CRRT), but pharmacokinetic data for tigecycline in patients receiving CRRT are lacking. METHODS: Eleven patients mainly with intra-abdominal infections receiving either continuous veno-venous hemodialysis (CVVHD, n = 8) or hemodiafiltration (CVVHDF, n = 3) were enrolled, and plasma as well as effluent samples were collected according to a rich sampling schedule. Total and free tigecycline was determined by ultrafiltration and high-performance liquid chromatography (HPLC)-UV. Population pharmacokinetic modeling using NONMEM® 7.4 was used to determine the pharmacokinetic parameters as well as the clearance of CVVHD and CVVHDF. Pharmacokinetic/pharmacodynamic target attainment analyses were performed to explore the potential need for dose adjustments of tigecycline in CRRT. RESULTS: A two-compartment population pharmacokinetic (PK) model was suitable to simultaneously describe the plasma PK and effluent measurements of tigecycline. Tigecycline dialysability was high, as indicated by the high mean saturation coefficients of 0.79 and 0.90 for CVVHD and CVVHDF, respectively, and in range of the concentration-dependent unbound fraction of tigecycline (45-94%). However, the contribution of CRRT to tigecycline clearance (CL) was only moderate (CLCVVHD: 1.69 L/h, CLCVVHDF: 2.71 L/h) in comparison with CLbody (physiological part of the total clearance) of 18.3 L/h. Bilirubin was identified as a covariate on CLbody in our collective, reducing the observed interindividual variability on CLbody from 58.6% to 43.6%. The probability of target attainment under CRRT for abdominal infections was ≥ 0.88 for minimal inhibitory concentration (MIC) values ≤ 0.5 mg/L and similar to patients without AKI. CONCLUSIONS: Despite high dialysability, dialysis clearance displayed only a minor contribution to tigecycline elimination, being in the range of renal elimination in patients without AKI. No dose adjustment of tigecycline seems necessary in CRRT. TRIAL REGISTRATION: EudraCT, 2012-005617-39 . Registered on 7 August 2013.

STRONG MILITARY FAMILIES INTERVENTION ENHANCES PARENTING REFLECTIVITY AND REPRESENTATIONS IN FAMILIES WITH YOUNG CHILDREN.

Military families face many challenges due to deployment and parental separation, and this can be especially difficult for families with young children. The Strong Military Families (SMF) intervention is for military families with young children, and consists of two versions: the Multifamily Group, and a Home-based psychoeducational written materials program. The Multifamily Group was designed to enhance positive parenting through both educational components and in vivo feedback and support during separations and reunions between parents and children (n = 78 parents). In the present study, we examine parenting reflectivity and mental representations in mothers versus fathers in military families, service members versus civilian spouses/parenting partners, and before versus after participation in the SMF Multifamily Group and Home-based interventions. Parenting reflectivity and mental representations were coded from the Working Model of the Child Interview (WMCI; C.H. Zeanah & D. Benoit, 1995). Results suggest that neither parenting reflectivity nor WMCI typology differs between mothers and fathers in military families, or between service members and civilian parenting partners. Furthermore, there was substantial stability in parenting reflectivity and WMCI typology from baseline to posttest, but participation in the Multifamily Group, relative to Home-based, was associated with improvements in both parenting reflectivity and WMCI ratings from baseline to postintervention.

[Pharmacokinetics and pharmacodynamics of antibiotic therapy]. / Pharmakokinetik und Pharmakodynamik der Antibiotikatherapie.

Antibiotic agents are crucial pillars in intensive care medicine and must be used rationally and sensibly. In the case of critically ill patients optimal dosing with respect to pharmacokinetic and pharmacodynamic principles (PK/PD) can be vital. Preclinical results demonstrated important differences between antibiotic classes and gave rise to differing clinical dosing strategies, e.g. high dose once daily regimens for aminoglycosides or extended/continuous infusion of betalactams. Critically ill patients with altered pharmacokinetic parameters and infections by pathogens with low susceptibility are most likely to benefit from PK/PD-guided therapy.

Plastid transformation in lettuce (Lactuca sativa L.) by polyethylene glycol treatment of protoplasts.

A detailed protocol for PEG-mediated plastid transformation of Lactuca sativa cv. Flora, using leaf protoplasts, is described. Successful plastid transformation using protoplasts requires a large number of viable cells, high plating densities, and an efficient regeneration system. Transformation was achieved using a vector that targets genes to the trnI/trnA intergenic region of the lettuce plastid genome. The aadA gene, encoding an adenylyltransferase enzyme that confers spectinomycin resistance, was used as a selectable marker. With the current method, the expected transformation frequency is 1-2 spectinomycin-resistant cell lines per 10(6) viable protoplasts. Fertile, diploid, homoplasmic, plastid-transformed lines were obtained. Transmission of the plastid-encoded transgene to the T1 generation was demonstrated.

[Strategies to avoid antibiotic resistance]. / Strategien zur Vermeidung von Antibiotikaresistenzen.

Antibiotics are used very frequently in critically ill patients as a causal and often life-saving treatment; however, the high density of use of broad spectrum antibiotics contributes to a further deterioration in resistance trends, which makes a rational prescription behavior mandatory. This particularly includes measures which lead to the reduction of antibiotic use, i.e. rigorous indications, targeted de-escalation and limited duration. For optimal efficacy of a necessary treatment the integration of pharmacokinetic and pharmacodynamic principles can be helpful.

Omeprazole impairs the absorption of mycophenolate mofetil but not of enteric-coated mycophenolate sodium in healthy volunteers.

In 2 crossover studies, 12 healthy volunteers (6 male/6 female) received a single oral dose of mycophenolate mofetil (MMF) 1000 mg or an equimolar dose of enteric-coated mycophenolate sodium (EC-MPS) 720 mg fasting with and without coadministered omeprazole 20 mg bid. The plasma concentrations of mycophenolic acid (MPA) and of the inactive metabolite mycophenolic acid glucuronide (MPA-G) were measured by high-performance liquid chromatography (HPLC). In addition, dissolution of MMF 500 mg or EC-MPS 360 mg tablets was determined using an USP paddle apparatus in aqueous buffer of pH 1 to 7. The bioavailability of MPA following administration of MMF or EC-MPS was similar except for the time to peak concentration, which was longer in the EC-MPS group. Concomitant treatment with omeprazole lowered significantly C(max) and AUC(12h) of MPA following administration of MMF. The pharmacokinetics of EC-MPS was not affected. Dissolution of MMF in aqueous buffer decreased dramatically at pH above 4.5. The EC-MPS tablet was stable up to pH 5. Above, EC-MPS was quantitatively disintegrated and MPS quantitatively dissolved. There is strong evidence that impaired absorption of MMF with concomitant proton pump inhibitors is due to incomplete dissolution of MMF in the stomach at elevated pH.

Response to imported case of Marburg hemorrhagic fever, the Netherland.

On July 10, 2008, Marburg hemorrhagic fever was confirmed in a Dutch patient who had vacationed recently in Uganda. Exposure most likely occurred in the Python Cave (Maramagambo Forest), which harbors bat species that elsewhere in Africa have been found positive for Marburg virus. A multidisciplinary response team was convened to perform a structured risk assessment, perform risk classification of contacts, issue guidelines for follow-up, provide information, and monitor the crisis response. In total, 130 contacts were identified (66 classified as high risk and 64 as low risk) and monitored for 21 days after their last possible exposure. The case raised questions specific to international travel, postexposure prophylaxis for Marburg virus, and laboratory testing of contacts with fever. We present lessons learned and results of the follow-up serosurvey of contacts and focus on factors that prevented overreaction during an event with a high public health impact.

Front-illuminated versus back-illuminated photon-counting CCD-based gamma camera: important consequences for spatial resolution and energy resolution.

Charge-coupled devices (CCDs) coupled to scintillation crystals can be used for high-resolution imaging with x-rays and gamma rays. When the CCD images can be read out fast enough, the energy and interaction position of individual gamma quanta can be estimated by a real-time image analysis of the scintillation light flashes ('photon-counting mode'). The electron-multiplying CCD (EMCCD) is well suited for fast read out, since even at high frame rates it has extremely low read-out noise. Back-illuminated (BI) EMCCDs have much higher quantum efficiency than front-illuminated (FI) EMCCDs. Here we compare the spatial and energy resolution of gamma cameras based on FI and BI EMCCDs. The CCDs are coupled to a 1000 microm thick columnar CsI(Tl) crystal for the purpose of Tc-99m and I-125 imaging. Intrinsic spatial resolutions of 44 microm for I-125 and 49 microm for Tc-99m were obtained when using a BI EMCCD, which is an improvement by a factor of about 1.2-2 over the FI EMCCD. Furthermore, in the energy spectrum of the BI EMCCD, the I-125 signal could be clearly separated from the background noise, which was not the case for the FI EMCCD. The energy resolution of a BI EMCCD for Tc-99m was estimated to be approximately 36 keV, full width at half maximum, at 141 keV. The excellent results for the BI EMCCD encouraged us to investigate the cooling requirements for our setup. We have found that for the BI EMCCD, the spatial and energy resolution, as well as image noise, remained stable over a range of temperatures from -50 degrees C to -15 degrees C. This is a significant advantage over the FI EMCCD, which suffered from loss of spatial and especially energy resolution at temperatures as low as -40 degrees C. We conclude that the use of BI EMCCDs may significantly improve the imaging capabilities and the cost efficiency of CCD-based high-resolution gamma cameras.

Stable plastid transformation in lettuce (Lactuca sativa L.).

Although plastid transformation in higher plants was first demonstrated in the early 1990s it is only recently that the technology is being extended to a broader range of species. To date, the production of fertile transplastomic plants has been reported for tobacco, tomato, petunia, soybean, cotton and Lesquerella fendleri (Brassicaceae). In this study we demonstrate a polyethylene glycol-mediated plastid transformation system for lettuce that generates fertile, homoplasmic, plastid-transformed lines. Transformation was achieved using a vector that targets genes to the trnA/trnI intergenic region of the lettuce plastid genome employing the aadA gene as a selectable marker against spectinomycin. Spectinomycin resistance and heterologous gene transcription were shown in T(1) plants derived from self-pollinated primary regenerants demonstrating transmission of the plastid-encoded transgene to the first seed generation. Crossing with male sterile wild-type lettuce showed that spectinomycin resistance was not transmitted via pollen. Constructs containing the gfp gene showed plastid-based expression of green fluorescent protein. The lettuce plastid could have potential both as a production and a delivery system for edible human therapeutic proteins.

[Ringer solution: osmolarity and composition revisited]. / Le soluté de Ringer: un standard "isotonique" discutable.

The composition of Ringer solution, a crystalloid fluid that is often used in anaesthesia and intensive care, varies depending on the manufacturer. The knowledge of the actual content in electrolytes and of the characteristics of this fluid is necessary before it is used. We call attention to a certain Ringer solution (Ringer Maco Pharma, Maco Pharma), for which the manufacturer's information about the tonicity and the osmolarity was incorrect. Contrary to what is written on the bag and in the product description (isotonicity, osmolarity of 276.8 mOsm/l), the theoretical osmolarity was 221.4 mOsm/l and the measured osmolality was about 208 mmol/kg, exposing the hypotonic characteristics of this fluid. The use of this product is potentially dangerous in patients with pathologies where the infusion of free water is especially badly supported.

Low dose thalidomide in patients with relapsed or refractory multiple myeloma.

Remarkable results of the treatment of refractory multiple myeloma with thalidomide have been reported. In most preceding studies, the given thalidomide dose was escalated to a maximum tolerated dose of up to 800 mg/d. The frequency of adverse effects correlates with dose intensity. Since a significant gain of therapeutic effects could not be observed as thalidomide dosage was escalated, the optimal dose of thalidomide remains to be determined. We report the results of a study with low dose thalidomide (median administered dose 100 mg/d, range 50-400 mg/d). Twenty-four relapsed (n = 19) or resistant (n = 5) multiple myeloma patients were included in the study. Twelve patients (50%) received thalidomide as monotherapy, 8 patients (33%) received a combination of thalidomide and dexamethasone (every 4 weeks 40 mg/day for 4 days) and 4 patients (17%) who were resistant to vincristine, doxorubicin, dexamethasone (VAD) received VAD combined with thalidomide. Overall, a response was observed in 12 patients (50%). Of the 12 patients treated with low dose thalidomide alone 5 (42%) responded, of the 8 patients who received a combination of thalidomide and dexamethasone 5 (63%) responded and of the 4 patients who had thalidomide in addition to VAD 2 patients (50%) responded. In 3 patients, thalidomide treatment had to be discontinued because of side effects and 1 patient died before response could be assessed. We conclude that low dose thalidomide is an effective and safe rescue therapy in relapsing or refractory multiple myeloma. Response to thalidomide might be dependent on prognostic parameters and tumor burden. To answer these questions larger prospective studies are necessary.

Arsenic trioxide: acute promyelocytic leukemia and beyond.

Arsenic containing treatments have a history of over two millenniums. Recently, arsenic trioxide (As2O3) has been introduced into the treatment of both de now and relapsed acute promyelocytic leukemia (APL), with remarkable clinical success. Several investigations using both freshly isolated APL blast cells as well as APL-derived tumor cell lines have shown that the main mechanism by which As2O3 exerts its antileukemic activity in APL is induction of apoptosis in the leukemic cell population. Recently, it has become evident that the apoptotic effects of As2O3 are not restricted to APL cells but may also be observed in malignant cells of non-APL origin. In the present review, history, current clinical use as well as future perspectives of As2O3 therapy in both hematologic and solid malignancies are discussed, with special emphasis being put on the potential future role of As2O3 in the treatment of non-APL tumors. Of particular importance, enhancing agents suited to increase As2O3-sensitivity in less sensitive tumors (e.g. ascorbic acid) are also addressed.

Measuring qualitative aspects of preschool boys' noncompliance: the Response Style Questionnaire (RSQ).

Child noncompliance is a core maladjustment factor in current clinical models of aggression and antisocial development. However, little is known about the relations among qualitative aspects of child noncompliance and aggressive maladjustment. The authors developed the Response Style Questionnaire, an instrument designed to measure the multidimensional qualities of child noncompliance, and tested its validity and reliability. Tests of internal validity provided a five-factor solution, featuring distinctions in noncompliance quality between and among skilled noncompliance (verbally skilled and emotionally regulated) and unskilled noncompliance (overt/confrontational, covert/sneaky, and emotionally labile). Theory-driven tests of external validity using peer-adjustment variables as criteria provided discriminant prediction (a) among qualitatively distinct aspects of noncompliance and (b) between noncompliance qualities and rate. Discussion focuses on a modified view of the nature and role of noncompliance in aggressive and antisocial development.