Test-enhanced learning of clinical reasoning: a crossover randomised trial

CONTEXT: Clinical reasoning is an essential skill, the foundations of which should be acquired during undergraduate medical education. Student performance in clinical reasoning can be assessed using key feature examinations. However, within a paradigm of test-enhanced learning, such examinations may also be used to enhance long-term retention of procedural knowledge relevant to clinical reasoning. OBJECTIVES: This study tested the hypothesis that repeated testing with key feature questions is more effective than repeated case-based learning in fostering clinical reasoning. METHODS: In this randomised crossover trial, Year 4 medical students attended 10 weekly computer-based seminars during which patient case histories covering general medical conditions were displayed. The presentation format was switched between groups every week. In the control condition, students studied long case narratives. The intervention condition used the same content but augmented case presentation with a sequence of key feature questions. Using a within-subjects design, student performance on intervention and control items was assessed at 13 weeks (exit examination) and 9 months (retention test) after the first day of term. RESULTS: A total of 87 of 124 eligible students provided complete data for the longitudinal analysis (response rate: 70.2%). In the retention test, mean ± standard deviation student scores on intervention items were significantly higher than those on control items (56.0 ± 25.8% versus 48.8 ± 24.7%; p < 0.001). The results remained unchanged after accounting for exposure time in a linear regression analysis that also adjusted for sex and general student performance levels. CONCLUSIONS: This is the first study to demonstrate an effect of test-enhanced learning on clinical reasoning as assessed with key feature questions. In this randomised trial, repeated testing was more effective than repeated case-based learning alone. Curricular implementation of longitudinal key feature testing may considerably enhance student learning outcomes in relevant aspects of clinical medicine

Diffusion-weighted magnetic resonance imaging using a preclinical 1 T PET/MRI in healthy and tumor-bearing rats

Background: Hybrid positron emission tomography and magnetic resonance imaging (PET/MRI) scanners are increasingly used for both clinical and preclinical imaging. Especially functional MRI sequences such as diffusionweighted imaging (DWI) are of great interest as they provide information on a molecular level, thus, can be used as surrogate biomarkers. Due to technical restrictions, MR sequences need to be adapted for each system to perform reliable imaging. There is, to our knowledge, no suitable DWI protocol for 1 Tesla PET/MRI scanners. We aimed to establish such DWI protocol with focus on the choice of b values, suitable for longitudinal monitoring of tumor characteristics in a rat liver tumor model. Material and methods: DWI was first performed in 18 healthy rat livers using the scanner-dependent maximum of 4 b values (0, 100, 200, 300 s/mm2). Apparent diffusion coefficients (ADC) were calculated from different b value combinations and compared to the reference measurement with four b values. T2-weighted MRI and optimized DWI with best agreement between accuracy, scanning time, and system performance stability were used to monitor orthotopic hepatocellular carcinomas (HCC) in five rats of which three underwent additional 2-deoxy-2-(18F)fluoro-D-glucose(FDG)-PET imaging. ADCs were calculated for the tumor and the surrounding liver parenchyma and verified by histopathological analysis. Results: Compared to the reference measurements, the combination b = 0, 200, 300 s/mm2 showed the highest correlation coefficient (rs = 0.92) and agreement while reducing the acquisition time. However, measurements with less than four b values yielded significantly higher ADCs (p < 0.001). When monitoring the HCC, an expected drop of the ADC was observed over time. These findings were paralleled by FDG-PET showing both an increase in tumor size and uptake heterogeneity. Interestingly, surrounding liver parenchyma also showed a change in ADC values revealing varying levels of inflammation by immunohistochemistry. Conclusion: We established a respiratory-gated DWI protocol for a preclinical 1 T PET/MRI scanner allowing to monitor growth-related changes in ADC values of orthotopic HCC liver tumors. By monitoring the changes in tumor ADCs over time, different cellular stages were described. However, each study needs to adapt the protocol further according to their question to generate best possible results

Bone Morphogenetic Protein (BMP)-7 expression is decreased in human hypertensive nephrosclerosis

Background: Bone Morphogenetic Protein (BMP)-7 is protective in different animal models of acute and chronic kidney disease. Its role in human kidneys, and in particular hypertensive nephrosclerosis, has thus far not been described. Methods: BMP-7 mRNA was quantified using real-time PCR and localised by immunostaining in tissue samples from normal and nephrosclerotic human kidneys. The impact of angiotensin (AT)-II and the AT-II receptor antagonist telmisartan on BMP-7 mRNA levels and phosphorylated Smad 1/5/8 (pSmad 1/5/8) expression was quantified in proximal tubular cells (HK-2). Functional characteristics of BMP-7 were evaluated by testing its influence on TGF-b induced epithelial-to-mesenchymal transition (EMT), expression of TGF-b receptor type I (TGF-bRI) and phosphorylated Smad 2 (pSmad 2) as well as on TNF-a induced apoptosis of proximal tubular cells. Results: BMP-7 was predominantly found in the epithelia of the distal tubule and the collecting duct and was less abundant in proximal tubular cells. In sclerotic kidneys, BMP-7 was significantly decreased as demonstrated by real-time PCR and immunostaining. AT-II stimulation in HK-2 cells led to a significant decrease of BMP-7 and pSmad 1/5/8, which was partially ameliorated upon co-incubation with telmisartan. Only high concentrations of BMP-7 (100 ng/ml) were able to reverse TNF-a-induced apoptosis and TGF-b-induced EMT in human proximal tubule cells possibly due to a decreased expression of TGF-bRI. In addition, BMP-7 was able to reverse TGF-b-induced phosphorylation of Smad 2. Conclusions: The findings suggest a protective role for BMP-7 by counteracting the TGF-b and TNF-a-induced negative effects. The reduced expression of BMP-7 in patients with hypertensive nephrosclerosis may imply loss of protection and regenerative potential necessary to counter the disease

Urine E-cadherin: A Marker for early detection of kidney injury in diabetic patients.

Diabetic nephropathy (DN) is the main reason for end-stage renal disease. Microalbuminuria as the non-invasive available diagnosis marker lacks specificity and gives high false positive rates. To identify and validate biomarkers for DN, we used in the present study urine samples from four patient groups: diabetes without nephropathy, diabetes with microalbuminuria, diabetes with macroalbuminuria and proteinuria without diabetes. For the longitudinal validation, we recruited 563 diabetic patients and collected 1363 urine samples with the clinical data during a follow-up of 6 years. Comparative urinary proteomics identified four proteins Apolipoprotein A-I (APOA1), Beta-2-microglobulin (B2M), E-cadherin (CDH1) and Lithostathine-1-alpha (REG1A), which differentiated with high statistical strength (p < 0.05) between DN patients and the other groups. Label-free mass spectrometric quantification of the candidates confirmed the discriminatory value of E-cadherin and Lithostathine-1-alpha (p < 0.05). Immunological validation highlighted E-cadherin as the only marker able to differentiate significantly between the different DN stages with an area under the curve (AUC) of 0.85 (95%-CI: [0.72, 0.97]). The analysis of the samples from the longitudinal study confirmed the prognostic value of E-cadherin, the critical increase in urinary E-cadherin level was measured 20 ± 12.5 months before the onset of microalbuminuria and correlated significantly (p < 0.05) with the glomerular filtration rate measured by estimated glomerular filtration rate (eGFR)

Monitoring tools for DevOps and microservices: A systematic grey literature review

Microservice-based systems are usually developed according to agile practices like DevOps, which enables rapid and frequent releases to promptly react and adapt to changes. Monitoring is a key enabler for these systems, as they allow to continuously get feedback from the field and support timely and tailored decisions for a quality-driven evolution. In the realm of monitoring tools available for microservices in the DevOps-driven development practice, each with different features, assumptions, and performance, selecting a suitable tool is an as much difficult as impactful task. This article presents the results of a systematic study of the grey literature we performed to identify, classify and analyze the available monitoring tools for DevOps and microservices. We selected and examined a list of 71 monitoring tools, drawing a map of their characteristics, limitations, assumptions, and open challenges, meant to be useful to both researchers and practitioners working in this area. Results are publicly available and replicable

Does the proteasome inhibitor bortezomib sensitize to DNA-damaging therapy in gastroenteropancreatic neuroendocrine neoplasms? - A preclinical assessment in vitro and in vivo

BACKGROUND: Well-differentiated gastroenteropancreatic neuroendocrine neoplasms are rare tumors with a slow proliferation. They are virtually resistant to many DNA-damaging therapeutic approaches, such as chemo- and external beam therapy, which might be overcome by DNA damage inhibition induced by proteasome inhibitors such as bortezomib. METHODS AND RESULTS: In this study, we assessed several combined treatment modalities in vitro and in vivo. By cell-based functional analyses, in a 3D in ovo and an orthotopic mouse model, we demonstrated sensitizing effects of bortezomib combined with cisplatin, radiation and peptide receptor radionuclide therapy (PRRT). By gene expression profiling and western blot, we explored the underlying mechanisms, which resulted in an impaired DNA damage repair. Therapy-induced DNA damage triggered extrinsic proapoptotic signaling as well as the induction of cell cycle arrest, leading to a decreased vital tumor volume and altered tissue composition shown by magnetic resonance imaging and F-18-FDG-PET in vivo, however with no significant additional benefit related to PRRT alone. CONCLUSIONS: We demonstrated that bortezomib has short-term sensitizing effects when combined with DNA damaging therapy by interfering with DNA repair in vitro and in ovo. Nevertheless, due to high tumor heterogeneity after PRRT in long-term observations, we were not able to prove a therapeutic advantage of bortezomib-combined PRRT in an in vivo mouse model

Experience with model-based performance, reliability and adaptability assessment of a complex industrial architecture

In this paper, we report on our experience with the application of validated models to assess performance, reliability, and adaptability of a complex mission critical system that is being developed to dynamically monitor and control the position of an oil-drilling platform. We present real-time modeling results that show that all tasks are schedulable. We performed stochastic analysis of the distribution of task execution time as a function of the number of system interfaces. We report on the variability of task execution times for the expected system configurations. In addition, we have executed a system library for an important task inside the performance model simulator. We report on the measured algorithm convergence as a function of the number of vessel thrusters. We have also studied the system architecture adaptability by comparing the documented system architecture and the implemented source code. We report on the adaptability findings and the recommendations we were able to provide to the system’s architect. Finally, we have developed models of hardware and software reliability. We report on hardware and software reliability results based on the evaluation of the system architecture

The mechanisms of pharmacokinetic food-drug interactions - A perspective from the UNGAP group

The simultaneous intake of food and drugs can have a strong impact on drug release, absorption, distribution, metabolism and/or elimination and consequently, on the efficacy and safety of pharmacotherapy. As such, food-drug interactions are one of the main challenges in oral drug administration. Whereas pharmacokinetic (PK) food-drug interactions can have a variety of causes, pharmacodynamic (PD) food-drug interactions occur due to specific pharmacological interactions between a drug and particular drinks or food. In recent years, extensive efforts were made to elucidate the mechanisms that drive pharmacokinetic food-drug interactions. Their occurrence depends mainly on the properties of the drug substance, the formulation and a multitude of physiological factors. Every intake of food or drink changes the physiological conditions in the human gastrointestinal tract. Therefore, a precise understanding of how different foods and drinks affect the processes of drug absorption, distribution, metabolism and/or elimination as well as formulation performance is important in order to be able to predict and avoid such interactions. Furthermore, it must be considered that beverages such as milk, grapefruit juice and alcohol can also lead to specific food-drug interactions. In this regard, the growing use of food supplements and functional food requires urgent attention in oral pharmacotherapy. Recently, a new consortium in Understanding Gastrointestinal Absorption-related Processes (UNGAP) was established through COST, a funding organisation of the European Union supporting translational research across Europe. In this review of the UNGAP Working group "Food-Drug Interface", the different mechanisms that can lead to pharmacokinetic food-drug interactions are discussed and summarised from different expert perspectives

INFOGEST static in vitro simulation of gastrointestinal food digestion

peer-reviewedSupplementary information is available at http://dx.doi.org/10.1038/s41596-018-0119-1 or https://www.nature.com/articles/s41596-018-0119-1#Sec45.Developing a mechanistic understanding of the impact of food structure and composition on human health has increasingly involved simulating digestion in the upper gastrointestinal tract. These simulations have used a wide range of different conditions that often have very little physiological relevance, and this impedes the meaningful comparison of results. The standardized protocol presented here is based on an international consensus developed by the COST INFOGEST network. The method is designed to be used with standard laboratory equipment and requires limited experience to encourage a wide range of researchers to adopt it. It is a static digestion method that uses constant ratios of meal to digestive fluids and a constant pH for each step of digestion. This makes the method simple to use but not suitable for simulating digestion kinetics. Using this method, food samples are subjected to sequential oral, gastric and intestinal digestion while parameters such as electrolytes, enzymes, bile, dilution, pH and time of digestion are based on available physiological data. This amended and improved digestion method (INFOGEST 2.0) avoids challenges associated with the original method, such as the inclusion of the oral phase and the use of gastric lipase. The method can be used to assess the endpoints resulting from digestion of foods by analyzing the digestion products (e.g., peptides/amino acids, fatty acids, simple sugars) and evaluating the release of micronutrients from the food matrix. The whole protocol can be completed in ~7 d, including ~5 d required for the determination of enzyme activities.COST action FA1005 INFOGEST (http://www.cost-infogest.eu/ ) is acknowledged for providing funding for travel, meetings and conferences (2011-2015). The French National Institute for Agricultural Research (INRA, www.inra.fr) is acknowledged for their continuous support of the INFOGEST network by organising and co-funding the International Conference on Food Digestion and workgroup meeting