Evaluation of medical decision support systems (DDX generators) using real medical cases of varying complexity and origin.

BACKGROUND: Medical decision support systems (CDSSs) are increasingly used in medicine, but their utility in daily medical practice is difficult to evaluate. One variant of CDSS is a generator of differential diagnoses (DDx generator). We performed a feasibility study on three different, publicly available data sets of medical cases in order to identify the frequency in which two different DDx generators provide helpful information (either by providing a list of differential diagnosis or recognizing the expert diagnosis if available) for a given case report. METHODS: Used data sets were n = 105 cases from a web-based forum of telemedicine with real life cases from Afghanistan (Afghan data set; AD), n = 124 cases discussed in a web-based medical forum (Coliquio data set; CD). Both websites are restricted for medical professionals only. The third data set consisted 50 special case reports published in the New England Journal of Medicine (NEJM). After keyword extraction, data were entered into two different DDx generators (IsabelHealth (IH), Memem7 (M7)) to examine differences in target diagnosis recognition and physician-rated usefulness between DDx generators. RESULTS: Both DDx generators detected the target diagnosis equally successfully (all cases: M7, 83/170 (49%); IH 90/170 (53%), NEJM: M7, 28/50 (56%); IH, 34/50 (68%); differences n.s.). Differences occurred in AD, where detection of an expert diagnosis was less successful with IH than with M7 (29.7% vs. 54.1%, p = 0.003). In contrast, in CD IH performed significantly better than M7 (73.9% vs. 32.6%, p = 0.021). Congruent identification of target diagnosis occurred in only 46/170 (27.1%) of cases. However, a qualitative analysis of the DDx results revealed useful complements from using the two systems in parallel. CONCLUSION: Both DDx systems IsabelHealth and Memem7 provided substantial help in finding a helpful list of differential diagnoses or identifying the target diagnosis either in standard cases or complicated and rare cases. Our pilot study highlights the need for different levels of complexity and types of real-world medical test cases, as there are significant differences between DDx generators away from traditional case reports. Combining different results from DDx generators seems to be a possible approach for future review and use of the systems.

[Metabolic acidosis : Diagnosis and treatment]. / Metabolische Azidose : Diagnostik und Therapie.

Acid-base disorders and in particular metabolic acidosis are very common in critically ill patients and contribute significantly to morbidity and mortality. We shed light on the most common causes, the pathophysiology and treatments. Particular attention will be paid to the common practice of substituting sodium bicarbonate in the light of recent study results.

Renal complications of cancer therapies.

Cancer patients often exhibit preexisting renal impairment and are simultaneously at risk for developing further kidney injury due to direct or indirect complications of oncological therapies. The nature of kidney injury is highly dependent on the therapy regimen used, and the spectrum of possible kidney stressors has widened as a result of the development of new therapeutic modalities such as molecular therapy or immunotherapy. Indirect renal complications are often due to volume depletion or other therapy-related side effects. Direct toxicity from "classic" chemotherapy treatments such as cisplatin usually leads to acute tubular necrosis, whereas treatment with protein kinase inhibitors is more likely to cause disorders such as thrombotic microangiopathy. Immunotherapy often affects kidneys through the development of acute interstitial nephritis. Because of the high risk of nephrological complications in oncological patients, close monitoring of renal function and the early involvement of a nephrologist are strongly recommended.

Risk prediction of acute kidney injury by [TIMP-2]•[IGFBP7].

Acute kidney injury (AKI) is a common syndrome with increased mortality, a heavy burden of illness and high cost. The Kidney Disease Improving Global Outcomes (KDIGO) criteria for staging of AKI have been validated in large patient cohorts and classify AKI into three stages. In order to achieve prevention or early therapy, the focus of scientific interest is early detection and risk prediction of AKI. The combination of the two cell cycle arrest markers [TIMP-2]·[IGFBP7] in the urine shows good results in the risk prediction of AKI in different clinical settings (intensive care medicine, sepsis, cardiac surgery, emergency department). Clinical use is currently being tested in different randomized intervention studies.

High energy proton induced radiation damage of rare earth permanent magnet quadrupoles.

Permanent magnet quadrupoles (PMQs) are an alternative to common electromagnetic quadrupoles especially for fixed rigidity beam transport scenarios at particle accelerators. Using those magnets for experimental setups can result in certain scenarios, in which a PMQ itself may be exposed to a large amount of primary and secondary particles with a broad energy spectrum, interacting with the magnetic material and affecting its magnetic properties. One specific scenario is proton microscopy, where a proton beam traverses an object and a collimator in which a part of the beam is scattered and deflected into PMQs used as part of a diagnostic system. During the commissioning of the PRIOR (Proton Microscope for Facility for Antiproton and Ion Research) high energy proton microscope facility prototype at Gesellschaft für Schwerionenforschung in 2014, a significant reduction of the image quality was observed which was partially attributed to the demagnetization of the used PMQ lenses and the corresponding decrease of the field quality. In order to study this phenomenon, Monte Carlo simulations were carried out and spare units manufactured from the same magnetic material-single wedges and a fully assembled PMQ module-were deliberately irradiated by a 3.6 GeV intense proton beam. The performed investigations have shown that in proton radiography applications the above described scattering may result in a high irradiation dose in the PMQ magnets. This did not only decrease the overall magnetic strength of the PMQs but also caused a significant degradation of the field quality of an assembled PMQ module by increasing the parasitic multipole field harmonics which effectively makes PMQs impractical for proton radiography applications or similar scenarios.

Commissioning of the PRIOR proton microscope.

Recently, a new high energy proton microscopy facility PRIOR (Proton Microscope for FAIR Facility for Anti-proton and Ion Research) has been designed, constructed, and successfully commissioned at GSI Helmholtzzentrum für Schwerionenforschung (Darmstadt, Germany). As a result of the experiments with 3.5-4.5 GeV proton beams delivered by the heavy ion synchrotron SIS-18 of GSI, 30 µm spatial and 10 ns temporal resolutions of the proton microscope have been demonstrated. A new pulsed power setup for studying properties of matter under extremes has been developed for the dynamic commissioning of the PRIOR facility. This paper describes the PRIOR setup as well as the results of the first static and dynamic proton radiography experiments performed at GSI.

Vector-mediated overexpression of catalase A in the yeast Saccharomyces cerevisiae induces inclusion body formation.

To study the morphological effects of overexpression of catalase A in yeast, the gene coding for catalase A was introduced into Saccharomyces cerevisiae on a multicopy vector. After induction of microbody biogenesis and catalase A expression by growth on oleic acid as sole carbon source, cells were analyzed by immunofluorescence and immunoelectron microscopy. In addition, overexpression of catalase A was studied by quantitative immunoblotting and by activity measurement. Quantitative immunoblotting resulted in a 16-fold difference between immunoreactive material from transformed and non-transformed cells. An 18-fold increase of enzyme activity was measured in transformed cells due to overexpression of catalase A from plasmid pAH521. Immunofluorescent staining of semithin sections of Lowicryl HM20-embedded cells with anti-catalase localized peroxisomes and--at a low percentage--larger particles. By immunoelectron microscopy, these larger structures could be identified as agranular, electron-dense aggregates which are morphologically clearly distinct from the cytoplasm and not bounded by a membrane. These structures, which have been named inclusion bodies, contain catalase A but not other peroxisomal enzymes like thiolase. These findings suggest that cells are capable of compensating for overproduced proteins by formation of particular types of structures.

Negative regulation of transcription of the Saccharomyces cerevisiae catalase T (CTT1) gene by cAMP is mediated by a positive control element.

Transcription of the CTT1 (catalase T) gene of Saccharomyces cerevisiae is controlled by oxygen via heme, by nutrients via cAMP and by heat shock. Nitrogen limitation triggers a rapid, cycloheximide-insensitive derepression of the gene. Residual derepression in a cAMP-nonresponsive mutant with attenuated protein kinase activity (bcy1 tpk1w tpk2 tpk3) demonstrates the existence of an alternative, cAMP-independent nutrient signaling mechanism. Deletion analysis using CTT1-lacZ fusion genes revealed the contribution of multiple control elements to derepression, not all of which respond to the cAMP signal. A positive promoter element responding to negative control by cAMP was inactivated by deletion of a DNA region between base pairs -340 and -364. Upstream fragments including this element confer negative cAMP control to a LEU2-lacZ fusion gene. Northern analysis of CTT1 expression in the presence or absence of heme, in RAS2+ (high cAMP) and ras2 mutant (low cAMP) strains and in cells grown at low temperature (23 degrees C) and in heat-shocked cells (37 degrees C) shows that CTT1 is only induced to an appreciable extent when at least two of the three factors contributing to its expression (oxidative stress signaled by heme, nutrient starvation (low cAMP) and heat stress) activate the CTT1 promoter.

Co-ordinate control of synthesis of mitochondrial and non-mitochondrial hemoproteins: a binding site for the HAP1 (CYP1) protein in the UAS region of the yeast catalase T gene (CTT1).

Control of expression of the Saccharomyces cerevisiae CTT1 (catalase T) gene by the HAP1 (CYP1) gene, a mediator of heme control of mitochondrial cytochromes, was studied. Expression of a CTT1-lacZ fusion in a hap1 mutant showed that the CTT1 promoter is under HAP1 control. As demonstrated by a gel retardation assay, the HAP1 protein binds to a heme control region of the CTT1 gene. This binding in vitro is stimulated by hemin. The HAP1-binding sequence was localized by using DNA fragments spanning different regions, by DNase I footprinting and by methylation interference of DNA-protein binding. The binding site was compared to the HAP1-binding sequences previously characterized in detail (UAS1CYC1, UASCYC7). There is strikingly little similarity between the three sequences, which have only four of those 23 bp in common which are protected from DNase I digestion. However, the pattern of major and minor groove contacts in the complex is quite similar in all three cases. The results obtained show that there is true co-ordinate control of expression of mitochondrial cytochromes and at least some extra-mitochondrial hemoproteins. Heme acts as a metabolic signal in this coordination, which is mediated by the HAP1 protein.