VAEs with structured image covariance applied to compressed sensing MRI.

Objective.This paper investigates how generative models, trained on ground-truth images, can be used as priors for inverse problems, penalizing reconstructions far from images the generator can produce. The aim is that learned regularization will provide complex data-driven priors to inverse problems while still retaining the control and insight of a variational regularization method. Moreover, unsupervised learning, without paired training data, allows the learned regularizer to remain flexible to changes in the forward problem such as noise level, sampling pattern or coil sensitivities in MRI.Approach.We utilize variational autoencoders that generate not only an image but also a covariance uncertainty matrix for each image. The covariance can model changing uncertainty dependencies caused by structure in the image, such as edges or objects, and provides a new distance metric from the manifold of learned images.Main results.We evaluate these novel generative regularizers on retrospectively sub-sampled real-valued MRI measurements from the fastMRI dataset. We compare our proposed learned regularization against other unlearned regularization approaches and unsupervised and supervised deep learning methods.Significance.Our results show that the proposed method is competitive with other state-of-the-art methods and behaves consistently with changing sampling patterns and noise levels.

Reflectionless propagation of Manakov solitons on a line: A model based on the concept of transparent boundary conditions.

We consider the problem of the absence of backscattering in the transport of Manakov solitons on a line. The concept of transparent boundary conditions is used for modeling the reflectionless propagation of Manakov vector solitons in a one-dimensional domain. Artificial boundary conditions that ensure the absence of backscattering are derived and their numerical implementation is demonstrated.

Dirac particles in transparent quantum graphs: Tunable transport of relativistic quasiparticles in branched structures.

We consider the dynamics of relativistic spin-half particles in quantum graphs with transparent branching points. The system is modeled by combining the quantum graph concept with the one of transparent boundary conditions applied to the Dirac equation on metric graphs. Within such an approach, we derive simple constraints, which turn the usual Kirchhoff-type boundary conditions at the vertex equivalent to the transparent ones. Our method is applied to quantum star graph. An extension to more complicated graph topologies is straightforward.

Transparent nonlinear networks.

We consider the reflectionless transport of solitons in networks. The system is modeled in terms of the nonlinear Schrödinger equation on metric graphs, for which transparent boundary conditions at the branching points are imposed. This approach allows to derive simple constraints, which link the equivalent usual Kirchhoff-type vertex conditions to the transparent ones. Our method is applied to a metric star graph. An extension to more complicated graph topologies is straightforward.

Influences on students' empathy in medical education: an exploratory interview study with medical students in their third and last year.

BACKGROUND: Empathy is beneficial for patients and physicians. It facilitates treatment and improves physical and psychosocial outcomes. The therapeutic relevance of empathy emphasizes the need to help medical students develop their empathic abilities. Our study aimed to identify factors which promote or hinder the development and expression of empathy in medical students during the course of their studies. METHODS: We interviewed 24 medical students (six male and six female students in their 6th semester as well as six male and six female students in their final clinical year) using semi-structured interviews. The interviews were recorded, transcribed verbatim and analyzed using Braun & Clarke's thematic analysis. RESULTS: We identified four main themes influencing the development and expression of empathy. 1) Course of studies: hands-on-experience, role models, science and theory, and emphasis on the importance of empathy; 2) students: insecurities and lack of routine, increasing professionalism, previous work experiences, professional distance, mood, maturity, and personal level of empathy; 3) patients: "easy" and "difficult" patients including their state of health; and 4) surrounding conditions: time pressure/stress, work environment, and job dissatisfaction. CONCLUSIONS: The development and use of empathy could be promoted by increasing: hands-on-experiences, possibilities to experience the patient's point of view and offering patient contact early in the curriculum. Students need support in reflecting on their actions, behavior and experiences with patients. Instructors need time and opportunities to reflect on their own communication with and treatment of patients, on their teaching behavior, and on their function as role models for treating patients empathically and preventing stress. Practical experiences should be made less stressful for students. The current changes implemented in some medical school curriculums (e.g., in Germany) seem to go in the right direction by integrating patient contact early on in the curriculum and focusing more on teaching adequate communication and interaction behaviors.

Survival of patients who develop solid tumors following hematopoietic stem cell transplantation.

Allogeneic hematopoietic cell transplantation is associated with late adverse effects of therapy, including secondary solid cancers. Most reports address risk factors; however, outcomes after secondary solid cancer development are incompletely described. Our objective was to estimate survival probabilities for transplant recipients dependent on secondary solid cancer subtype. We used a previously identified and published cohort who developed secondary solid cancers following allogeneic transplant. Follow-up for these 112 previously identified patients was extended and their survival probabilities were studied. Median duration of follow-up from the development of secondary cancer for survivors was 11.9 years (range: 0.8-23.4) and 75% were followed >7.0 years. The 5- and 10-year overall survival probabilities were 50% (95% confidence interval (CI): 41-60) and 46% (95% CI: 37-57), respectively. Overall survival varied by secondary cancer type. Secondary cancer was the cause of death in most patients who died following development of melanoma, central nervous system, oral cavity, thyroid, lung, lower gastrointestinal tract and bone cancers. Extended follow-up allowed for the most comprehensive longitudinal evaluation to date of this rare condition. These findings will enhance clinicians' ability to predict outcomes and counsel transplant survivors who develop secondary solid cancers.

[Promotion of next generation primary care physicians: initiatives in the university training of medical students]. / Förderung des allgemeinmedizinischen Nachwuchses : Initiativen in der universitären Ausbildung von Medizinstudierenden.

BACKGROUND: There is, and will be a serious shortage of young primary care physicians in Germany. Initiatives at medical faculties focusing on primary care may increase the recruitment of young primary care physicians. OBJECTIVES: The present report describes national and international university initiatives, as well as programs for the recruitment of primary care physicians, and reports on their evaluation. METHODS: We searched medical data bases, journals and the internet using corresponding key words in the sense of a pragmatic review article. We also contacted experts who were questioned on this topic. RESULTS: Initiatives for increasing the recruitment of young general practitioners were identified at nine medical faculties in Germany. The underlying hypothesis of the existing programs is that the decision to become a primary care physician depends on the time point, extent and quality of the training at medical school. The decisive limitation of existing programs is that they have been sparsely evaluated. The available results from evaluations consistently indicate quite large positive effects on the recruitment rates; however, the underlying study designs are highly prone to bias. CONCLUSION: The identified initiatives can be grouped into three different models: (1) postgraduate studies, (2) specialized curricula for selected students with high interest in primary care and (3) longitudinal integration of primary care teaching in the obligatory curriculum. Different aspects, such as selection of the curricular model, definition of content, reimbursement of personnel and material expenses as well as evaluation are relevant to the planning and implementation of such initiatives.

In-process measuring of the electrical shunt resistance of laser-scribed thin-film stacks by nested circular scribes.

Laser scribing of functional thin-film stacks attracts increasing attention especially for applications of flexible electronics or photovoltaics. Laser can perform selective removal of the thin-film stacks that is essential for the isolation and interconnection of the solar cells. The optimization of the laser scribing process concerning the functional properties of the device requires customized characterization techniques minimizing side effects. The proposed and demonstrated nested circular laser scribing technique allows the in-process measurement of the electrical characteristics, e.g., the shunt formation due to laser scribing of the thin-film stack, minimizing secondary effects originating from aging, contacting, changing of sample characteristics, or alterations of the measurement conditions. This technique enables the identification of reliable and quick information on the changes of the solar cell characteristics by laser scribing as this is demonstrated in this work.

Combination of MEK and SRC inhibition suppresses melanoma cell growth and invasion.

The RAS-RAF-MEK-ERK pathway is deregulated in over 90% of malignant melanomas, and targeting MEK as a central kinase of this pathway is currently tested in clinical trials. However, dose-limiting side effects are observed, and MEK inhibitors that sufficiently reduce ERK activation in patients show a low clinical response. Apart from dose limitations, a reason for the low response to MEK targeting drugs is thought to be the upregulation of counteracting signalling cascades as a direct response to MEK inhibition. Therefore, understanding the biology of melanoma cells and the effects of MEK inhibition on these cells will help to identify new combinatorial approaches that are more potent and allow for lower concentrations of the drug being used. We have discovered that in melanoma cells MEK inhibition by selumetinib (AZD6244, ARRY-142886) or PD184352, while efficiently suppressing proliferation, stimulates increased invasiveness. Inhibition of MEK suppresses actin-cortex contraction and increases integrin-mediated adhesion. Most importantly, and surprisingly, MEK inhibition results in a significant increase in matrix metalloproteases (MMP)-2 and membrane-type 1-MMP expression. All together, MEK inhibition in melanoma cells induces a 'mesenchymal' phenotype that is characterised by protease-driven invasion. This mode of invasion is dependent on integrin-mediated adhesion, and because SRC kinases are the main regulators of this process, the SRC kinase inhibitor, saracatinib (AZD0530), completely abolished the MEK inhibitor-induced invasion. Moreover, the combination of saracatinib and selumetinib effectively suppressed the growth and invasion of melanoma cells in a 3D environment, suggesting that combined inhibition of MEK and SRC is a promising approach to improve the efficacy of targeting the ERK/MAP kinase pathway in melanoma.

Rheology of dilute acid hydrolyzed corn stover at high solids concentration.

The rheological properties of acid hydrolyzed corn stover at high solids concentration (20-35 wt.%) were investigated using torque rheometry. These materials are yield stress fluids whose rheological properties can be well represented by the Bingham model. Yield stresses increase with increasing solids concentration and decrease with increasing hydrolysis reaction temperature, acid concentration, and rheometer temperature. Plastic viscosities increase with increasing solids concentration and tend to decrease with increasing reaction temperature and acid concentration. The solids concentration dependence of the yield stress is consistent with that reported for other fibrous systems. The changes in yield stress with reaction conditions are consistent with observed changes in particle size. This study illustrates that torque rheometry can be used effectively to measure rheological properties of concentrated biomass.

Technical note: A rapid enzyme-linked immunosorbent assay blood test for pregnancy in dairy and beef cattle.

The ruminant trophoblast produces pregnancy-associated glycoproteins (PAG) that can be detected in the blood of pregnant animals. The objective was to determine the accuracy of a rapid ELISA PAG-based test for the purpose of pregnancy detection in cattle. Blood was sampled from dairy cattle (539 Holstein cows, 173 Holstein heifers, 73 Guernsey cows, 22 Guernsey heifers, and 12 Jersey heifers) and crossbred beef cattle (145 cows and 46 heifers) that were >or=25 d after insemination (range = 25 to 45 d for dairy and 29 to 56 d for beef). Cattle were examined by ultrasonography for detection of pregnancy within 2 d of blood collection. Whole blood or plasma was incubated in a polystyrene tube coated with a monoclonal PAG antibody for 15 min. The tubes were then washed and subjected to sequential incubations with a biotinylated polyclonal PAG antibody (15 min, followed by wash), a horseradish peroxidase-streptavidin solution (15 min, followed by wash), and a peroxidase substrate. Tubes were visually assessed for color after 15 min (clear solution = PAG negative, not pregnant; blue solution = PAG positive, pregnant). Total assay time was approximately 90 min. The ultrasound examination was used as the standard for pregnancy diagnosis. The sensitivity (99.8 +/- 0.2%), specificity (91.7 +/- 1.4%), and negative predictive value (99.7 +/- 0.3%) for the PAG test used in dairy cattle were similar for different breeds and for cows and heifers. The positive predictive value for the test was greater in dairy heifers than in dairy cows (96.5 +/- 1.4% vs. 90.5 +/- 1.7%, respectively). In beef cattle, the sensitivity (100%), specificity (92.3 +/- 3.0%), positive predictive value (95.0 +/- 2.0%), and negative predictive value (100%) for the PAG test were similar for cows and heifers. The accuracy of the test was not different for dairy and beef cattle. In conclusion, the rapid ELISA pregnancy test based on PAG was highly sensitive and specific for pregnancy detection in dairy and beef cattle.

[Effects of therapy goal oriented cognitive behavioural aftercare measures on therapy transfer following inpatient psychosomatic rehabilitation]. / Effekte therapiezielorientierter kognitiv-verhaltenstherapeutischer Nachsorgemassnahmen auf den Therapietransfer im Anschluss an eine stationäre psychosomatische Rehabilitationsbehandlung.

OBJECTIVE: After discharge from inpatient psychosomatic rehabilitation patients often face problems to transfer and stabilize the modifications they have achieved in the clinic. Using targeted outpatient aftercare interventions up to eight weeks after discharge from the inpatient programme we tried to support this transfer, thus enhancing treatment effectiveness. METHOD: The evaluation was carried out as a field experiment. Patients were matched into pairs and then allocated randomly to either a control or an experimental condition. The experimental group, which had participated in specific aftercare measures after inpatient therapy, was compared to the control group at "discharge from clinic" and "twelve weeks post-discharge" relative to a number of variables relevant in therapy outcome. RESULTS: Twelve weeks post-discharge patients who had participated in aftercare measures show significantly better progress relative to their physical and psychological complaints than patients in the control group. Also, they are more capable of coping with psychosocial demands of their everyday life. They experience better control of their symptoms and they are more successful in attaining the goals they have set for themselves for the time after discharge. CONCLUSIONS: The findings show that supplementing psychosomatic inpatient rehabilitation with specific aftercare measures will lead to better transfer and to increased effectiveness of psychosomatic rehabilitation. Also on account of our results, outpatient rehab aftercare programmes have in the meantime become a regular component of inpatient psychosomatic rehabilitation in Germany.

Preparation of encapsulated proteins dissolved in low viscosity fluids.

The majority of proteins are too large to be comprehensively examined by solution NMR methods, primarily because they tumble too slowly in solution. One potential approach to making the NMR relaxation properties of large proteins amenable to modern solution NMR techniques is to encapsulate them in a reverse micelle which is dissolved in a low viscosity fluid. Unfortunately, promising low viscosity fluids such as the short chain alkanes, supercritical carbon dioxide, and various halocarbon refrigerants all require the application of significant pressure to be kept liquefied at room temperature. Here we describe the design and use of a simple cost effective NMR tube suitable for the preparation of solutions of proteins encapsulated in reverse micelles dissolved in such fluids.

[Need for rehabilitation from the viewpoint of the general practitioner]. / Der Bedarf an Rehamassnahmen aus allgemeinärztlicher Sicht.

In Germany, the general practitioner plays an important role in the allocation process of rehabilitative measures. A survey concerning the questions of need, demand and effectiveness of medical rehabilitation measures as seen from the general practitioner's perspective in Hamburg, Schleswig-Holstein und Halle/Saale (n = 956) in 1999 shows that general practitioners have a rather positive attitude towards rehabilitation in general. With regard to the different measures within the rehabilitation system they show a differentiated opinion. As they see a large percentage of over- and underuse of rehabilitation they would appreciate that their information on the patient would be more intensively taken into account in the allocation process.

High-resolution NMR of encapsulated proteins dissolved in low-viscosity fluids.

The majority of known proteins are too large to be comprehensively examined by solution NMR methods, primarily because they tumble too slowly in solution. Here we introduce an approach to making the NMR relaxation properties of large proteins amenable to modern solution NMR techniques. The encapsulation of a protein in a reverse micelle dissolved in a low-viscosity fluid allows it to tumble as fast as a much smaller protein. The approach is demonstrated and validated with the protein ubiquitin encapsulated in reverse micelles prepared in a variety of alkane solvents.

An adjuvant afterloading brachytherapy device for use after orbital exenteration in patients with orbital malignancies.

In cases of malignant diseases situated within the orbit and threaten to extend beyond it, removal of the orbit and periorbital contents may be indicated, followed by adjuvant chemotherapy or irradiation. An effective radiotherapy device for treatment of residual or suspicious cancer in the enucleated orbit consists of an external-beam radiation source (60Co) and an intraoperatively fitted mould as a guide for the flexible afterloading tubes using a 192Ir source. Considering the physical dose distribution and the local situation, this therapy permits a high dose with homogeneous dose distribution to the target area of the orbit but also allows significant dose reduction to adjunctive critical structures. Four patients with different orbital malignancies were treated by means of a combination of percutaneous radiotherapy with afterloading brachytherapy following orbital exenteration. The individual mould of the orbital cavity is modeled at the end of the operation. The technique of radiotherapy, dose distribution, and follow-up of the disease are demonstrated. Orbital malignancies with an extremely poor prognosis may profit from the application of this combined radiotherapy to avoid supraradical surgical intervention.

Molecular recognition by calmodulin: pressure-induced reorganization of a novel calmodulin-peptide complex.

The interaction of apocalmodulin (apoCaM) with a peptide (Neurop) based on the primary sequence of the calmodulin-binding domain of neuromodulin has been studied by fluorescence spectroscopy. The 1:1 complex (12 microM) formed between apoCaM and the Neurop peptide is extremely sensitive to salt and is half dissociated in less than 0.1 M KCl, suggesting that electrostatic interactions contribute strongly to complex formation. Ion pair interactions are frequently sensitive to high hydrostatic pressure due to electrostriction effects in the solvated ion state. Application of high pressure to the apoCaM.Neurop complex causes a red shift of the Neurop tryptophan emission center of mass and a reduced residual anisotropy but with insignificant reduction in quantum yield. The transition is smooth, reversible, and apparently two-state with a midpoint pressure of approximately 0.8 kbar. The residual anisotropy, quantum yield, and center of mass of the emission spectrum are consistent with the movement of the tryptophan side chain to a more solvated, slightly less restricted environment upon the pressure-induced transition. The pressure effect is independent of the concentration of the complex. These and other data are consistent with the pressure-induced reorganization being a unimolecular event not requiring dissociation of the complex. A volume change of approximately 66 mL mol-1 and a free energy change of approximately 1.7 kcal mol-1 are associated with the reorganization. The residual interactions maintaining the complex under high pressure are characterized by low standard molar volume and/or high standard free energy changes upon disruption but are destroyed by 200 mM KCl. It is postulated that the main effect of salt on the complex at high pressure is to drive the collapse of the hydrophobic pocket to which the peptide is binding.

The energetics and dynamics of molecular recognition by calmodulin.

Amide hydrogen exchange has been used to examine the structural dynamics and energetics of the interaction of a peptide corresponding to the calmodulin binding domain of smooth muscle myosin light chain kinase with calcium-saturated calmodulin. Heteronuclear NMR 15N-1H correlation techniques were used to quantitate amide proton exchange rates of both 15N-labeled and unlabeled amide protons of the smMLCK peptide complexed to calmodulin. Hydrogen exchange slowing factors were determined for 18 of the 19 amide hydrogens and found to span 6 orders of magnitude. The first six residues of the bound peptide were found to have slowing factors near 1 and are considered not to be hydrogen bonded, consistent with the previously reported model for the structure of the peptide. The pattern of hydrogen exchange of hydrogen-bonded amide hydrogens is indicative of end-fraying behavior characteristic of helix-coil transitions. The effective statistical mechanical parameters revealed by the end fraying are consistent with exchange from a highly solvated state. However, the slowing factors of the first hydrogen-bonded amide hydrogens are large, indicating the requirement for a reorganization of the calmodulin-peptide complex before the helix-coil transitions leading to exchange can occur. Taken together, these observations suggest that the collapsed complex reorganizes with an associated free energy change of 5.5 kcal/mol to a more open state where the helical peptide is highly solvated and undergoes helix-coil transitions leading to exchange. The free energy difference between the most and least stable intrahelical amide hydrogen bonds of the bound peptide is estimated to be approximately 2.5 kcal/mol.(ABSTRACT TRUNCATED AT 250 WORDS)

The standard of care.

The professional standard of care has historically been defined in terms of the practice of reasonable, prudent physicians. In court, physicians are needed in most cases to testify as to what is the standard of practice and to verify the relevance of published materials that may be presented as being descriptive of the standard of care. Proposed standards have been published by many organizations and institutions. The medical literature also serves as a source of information concerning medical practices. Court cases may be decided in a way that suggests that the usual practices of physicians are inadequate.

Calmodulin interacts with amphiphilic peptides composed of all D-amino acids.

Calmodulin binds to amphiphilic, helical peptides of a variety of amino-acid sequences. These peptides are usually positively charged, although there is spectroscopic evidence that at least one neutral peptide binds. The complex between calmodulin and one of its natural target peptides, the binding site for calmodulin on smooth muscle myosin light-chain kinase (RS20), has been investigated by crystallography and NMR which have characterized the interactions between the ligand and the protein. From these data, it appears that the calmodulin-binding surface is sterically malleable and van der Waals forces probably dominate the binding. To explore further this apparently permissive binding, we investigated the chiral selectivity of calmodulin using synthesized analogues of melittin and RS20 that consisted of only D-amino acids. Fluorescence and NMR measurements show that D-melittin and D-RS20 both bind avidly to calmodulin, probably in the same general binding site as that for peptides having all L-amino acids. The calmodulin-peptide binding surface is therefore remarkably tolerant sterically. Our results suggest a potentially useful approach to the design of non-hydrolysable or slowly hydrolysable intracellular inhibitors of calmodulin.