Abstract: Clinical reasoning for acute dyspnoea: Comparison of final-year medical students from discipline- andcompetency-based undergraduate programmes.

Background: The global shift to competency-based medical education aims to improve the performance of itstrainees, including in the key competency domain of clinical reasoning. However, research on whether such educationactually improves clinical reasoning is sparse. The purpose of this study is to compare assessed clinical reasoningperformance in digitally presented cases of acute dyspnoea between final-year medical students from a traditional,discipline-based and those from an integrated, competency-based undergraduate programme.

Methods: A total of 60 medical students in their final-year clerkships participated in the study; 30 were from adiscipline-based programme, and 30 were from a competency-based programme of the same faculty. The studentscompleted a knowledge test consisting of 22 single choice items and a computer-based test of clinical reasoning withsix video-based case scenarios with different underlying diseases leading to dyspnoea. The operationalized measures ofclinical reasoning were the number and relevance of the diagnostic tests chosen, time to diagnosis and diagnosticaccuracy.

Results: The two groups did not differ in their knowledge of the acute dyspnoea content domain. With regard toclinical reasoning, the selection of relevant tests, time required to make a diagnosis and accuracy of the diagnosisvaried across the six case scenarios in both groups. However, the results from the measures of the clinical reasoningprocess did not differ between the students from the two types of undergraduate medical programmes. No significantdifferences were found with regard to the selection of relevant diagnostic tests (M = 63.8% vs. M = 62.8%), the time toa diagnosis (M = 128.7 s vs. M = 136.4 s) or the accuracy of diagnosis (M = 82.2% vs. M = 77.0%).

Conclusions: Key indicators of the clinical reasoning process, when assessed with objectively measured parameters,did not differ between final-year medical students from a traditional, discipline-based and those from an integrated,competency-based undergraduate programme in the domain of acute dyspnoea. The results substantiate and expandthose of previous studies based on subjective assessor ratings that showed limited change in the clinical reasoningperformance of medical students with competency-based undergraduate education.

Only half of patients with relapsed B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) currently survive with standard treatment protocols. Predicting individual patient responses to defined drugs prior to application would help therapy stratification and could improve survival. With the purpose to aid personalized targeted treatment approaches, we developed a human-zebrafish xenograft (ALL-ZeFiX) assay to predict drug response in a patient in 5 days. Leukemia blast cells were pericardially engrafted into transiently immunosuppressed Danio rerio embryos, and engrafted embryos treated for the test case, venetoclax, before single-cell dissolution for quantitative whole blast cell analysis. Bone marrow blasts from patients with newly diagnosed or relapsed BCP-ALL were successfully expanded in 60% of transplants in immunosuppressed zebrafish embryos. The response of BCP-ALL cell lines to venetoclax in ALL-ZeFiX assays mirrored responses in 2D cultures. Venetoclax produced varied responses in patient-derived BCP-ALL grafts, including two results mirroring treatment responses in two refractory BCP-ALL patients treated with venetoclax. Here we demonstrate proof-of-concept for our 5-day ALL-ZeFiX assay with primary patient blasts and the test case, venetoclax, which after expanded testing for further targeted drugs could support personalized treatment decisions within the clinical time window for decision-making.

Dear humans, you cannot see me with naked eyes,1 and yet you can no longer ignore my existence (Figure 1). My official title is long: Severe Acute Respiratory Syndrome‐Coronavirus‐2 (SARS‐CoV‐2). I am also known as nCoV, the 2019 Novel Coronavirus, or simply Corona. In early December 2019, I was making the usual rounds in a Wuhan food market in Hubei province in China. The market was thick with humans and nonhumans in proximity. I attached myself to a tiny droplet slipping inside ‘patient zero’, who sneezed, coughed, suffered from high temperature and breathing difficulty, and recovered after two weeks. ‘Patient zero’ thought I was an ordinary virus that caused the endemic, seasonal flu. It was not until I had multiplied in hundreds and thousands, and an unusually high number of pneumonia cases had been reported, that the global health authorities took notice (Heymann and Shindo 2020).

Aiming at the overall negative surface charge of bacteria, a new strategy of antibacterial agents based on large polymer‐modified graphene oxide (GO) sheets is assessed. The presented flexible, polycationic sheets match the size and charge density of the Escherichia coli surface charge density (2 × 1014 cm−2). These matching parameters create an unspecific but very strong bacteria adsorber by multivalent, electrostatic attraction. Their interaction with bacteria is visualized via atomic force and confocal microscopy and shows that they effectively bind and wrap around E. coli cells, and thereby immobilize them. The incubation of Gram‐negative and ‐positive bacteria (E. coli and methicillin‐resistant Staphylococcus aureus , MRSA) with these polycationic sheets leads to the inhibition of proliferation and a reduction of the colony forming bacteria over time. This new type of antibacterial agent acts in a different mode of action than classical biocides and could potentially be employed in medicinal, technical, or agriculture applications. The presented microsheets and their unspecific binding of cell interfaces could further be employed as adsorber material for bacterial filtration or immobilization for imaging, analysis, or sensor technologies.

This article studies the effects of uncertainty shocks on economic activity, focusing on inflation. Using a vector autoregression, I show that increased uncertainty has negative demand effects, reducing GDP and prices. I then consider standard New Keynesian models with Rotemberg‐type and Calvo‐type price rigidities. Despite the belief that the two schemes are equivalent, I show that they generate different dynamics in response to uncertainty shocks. In the Rotemberg model, uncertainty shocks decrease output and inflation, in line with the empirical results. By contrast, in the Calvo model, uncertainty shocks decrease output but raise inflation because of firms' precautionary pricing motive.

In this work, a full account of the authors’ synthetic studies is reported that culminated in the first synthesis of 13(14→8),14(8→7)diabeo‐steroid swinhoeisterol A as well as the related dankasterones A and B, 13(14→8)abeo‐steroids, and periconiastone A, a 13(14→8)abeo‐4,14‐cyclo‐steroid. Experiments are described in detail that provided further insight into the mechanism of the switchable radical framework reconstruction approach. By discussing failed strategies and tactics towards swinhoeisterol A, the successful route that also allowed an access to structurally closely related analogues, such as Δ22‐24‐epi‐swinhoeisterol A, is eventually presented.

Background: In epidemiology, causal inference and prediction modeling methodologies have been historically distinct. Directed Acyclic Graphs (DAGs) are used to model a priori causal assumptions and inform variable selection strategies for causal questions. Although tools originally designed for prediction are finding applications in causal inference, the counterpart has remained largely unexplored. The aim of this theoretical and simulation-based study is to assess the potential benefit of using DAGs in clinical risk prediction modeling.

Methods: We explore how incorporating knowledge about the underlying causal structure can provide insights about the transportability of diagnostic clinical risk prediction models to different settings. We further probe whether causal knowledge can be used to improve predictor selection in clinical risk prediction models.

Results: A single-predictor model in the causal direction is likely to have better transportability than one in the anticausal direction in some scenarios. We empirically show that the Markov Blanket, the set of variables including the parents, children, and parents of the children of the outcome node in a DAG, is the optimal set of predictors for that outcome.

Conclusions: Our findings provide a theoretical basis for the intuition that a diagnostic clinical risk prediction model including causes as predictors is likely to be more transportable. Furthermore, using DAGs to identify Markov Blanket variables may be a useful, efficient strategy to select predictors in clinical risk prediction models if strong knowledge of the underlying causal structure exists or can be learned.

Background: Evidence suggests that mobile health app use is beneficial for the prevention and management of type 2 diabetes (T2D) and its associated complications; however, population-based research on specific determinants of health app use in people with and without T2D is scarce.

Objective: This cross-sectional study aimed to provide population-based evidence on rates and determinants of health app use among adults with and without T2D, thereby covering a prevention perspective and a diabetes management perspective, respectively.

Methods: The study population included 2327 adults without a known diabetes diagnosis and 1149 adults with known T2D from a nationwide telephone survey in Germany conducted in 2017. Rates of smartphone ownership and health app use were estimated based on weighted sample proportions. Among smartphone owners, determinants of health app use were identified for both groups separately in multivariable logistic regression models. Sociodemographic factors, diabetes-related factors or indicators, psychological and health-related factors, and physician-provided information were selected as potential determinants.

Results: Among participants without known diabetes, 74.72% (1690/2327) were smartphone owners. Of those, 49.27% (717/1690) used health apps, most often to improve regular physical activity. Among participants with T2D, 42.26% (481/1149) were smartphone owners. Of those, 41.1% (171/481) used health apps, most commonly to target a healthy diet. Among people without known diabetes, determinants significantly (all P values <.05) associated with an increased likelihood of health app use compared with their reference group were as follows: younger and middle age of 18 to 44 or 45 to 64 years (odds ratios [ORs] 3.89; P<.001 and 1.76; P=.004, respectively), overweight or obesity (ORs 1.58; P<.001 and 2.07; P<.001, respectively), hypertension diagnosis (OR 1.31; P=.045), former or current smoking (ORs 1.51; P=.002 and 1.58; P<.001, respectively), perceiving health as very good (OR 2.21; P<.001), other chronic diseases (OR 1.48; P=.002), and having received health advice from a physician (OR 1.48; P<.001). A slight or high perceived diabetes risk (ORs 0.78; P=.04 and 0.23; P<.001, respectively) was significantly associated with a decreased likelihood of health app use. Among people with T2D, younger and middle age (18-64 years; OR 1.84; P=.007), female gender (OR 1.61; P=.02), and using a glucose sensor in addition or instead of a glucose meter (OR 2.74; P=.04) were significantly positively associated with health app use.

Conclusions: In terms of T2D prevention, age, diabetes-related risk factors, psychological and health-related factors, and medical health advice may inform app development for specific target groups. In addition, health professionals may encourage health app use when giving advice on health behaviors. Concerning T2D management, only a few determinants seem relevant for explaining health app use among people with T2D, indicating a need for more future research on which people with T2D use health apps and why.

Epithelial ovarian cancer (EOC) was previously shown to be associated with glycosylation changes of total serum and total IgG proteins. However, as a majority of previous studies analyzed released glycan profiles, still little is known about IgG subclass-specific alterations in ovarian cancer. Hence, in this study, we investigated EOC-related glycosylation changes of the three most abundant IgG subclasses, namely, IgG1, IgG2 and IgG3 isolated from sera of 87 EOC patients and 74 age-matched healthy controls. In order to separate IgG2 and IgG3, we performed a two-step affinity purification employing Protein A and Protein G Sepharose. After tryptic digestion, IgG glycopeptides were enriched and measured by MALDI-TOF-MS. Finally, EOC-related glycosylation changes were monitored at the level of total agalactosylation, monogalactosylation, digalactosylation, sialylation, bisection and fucosylation, which were calculated separately for each IgG subclass. Interestingly, aside from an EOC-related increase in agalactosylation/decrease in monogalactosylation and digalactosylation observed in all IgG subclasses, some subclass-specific trends were detected. Glycosylation of IgG1 was found to be most strongly affected in EOC, as it exhibited the highest number of significant differences between healthy controls and EOC patients. Specifically, IgG1 was the only subclass that showed a significant decrease in sialylation and a significant increase in fucosylation in EOC patients. Interestingly, IgG2 and IgG3 that were often investigated collectively in previous studies, were found to have distinct glycosylation patterns. IgG3 displayed stronger EOC-related increase in agalactosylation/decrease in digalactosylation and was characterized by notably higher sialylation, which consequently decreased in EOC patients. In conclusion, our study indicates that IgG subclasses exhibit subtly distinct glycosylation patterns of EOC-related alterations and that IgG1 and IgG3 agalactosylation show the strongest association with CA125, the routine diagnostic marker. Additionally, our results show that simultaneous analyses of IgG2 and IgG3 might lead to wrong conclusions as these two subclasses exhibit noticeably different glycosylation phenotypes.

Background: Patients with oligometastatic disease can potentially be cured by using an ablative therapy for all active lesions. Stereotactic body radiotherapy (SBRT) is a non-invasive treatment option that lately proved to be as effective and safe as surgery in treating lung metastases (LM). However, it is not clear which patients benefit most and what are the most suitable fractionation regimens. The aim of this study was to analyze treatment outcomes after single fraction radiosurgery (SFRS) and fractionated SBRT (fSBRT) in patients with lung oligometastases and identify prognostic clinical features for better survival outcomes.

Methods: Fifty-two patients with 94 LM treated with SFRS or fSBRT between 2010 and 2016 were analyzed. The characteristics of primary tumor, LM, treatment, toxicity profiles and outcomes were assessed. Kaplan-Meier and Cox regression analyses were used for estimation of local control (LC), overall survival (OS) and progression-free survival.

Results: Ninety-four LM in 52 patients were treated using SFRS/fSBRT with a median of 2 lesions per patient (range: 1-5). The median planning target volume (PTV)-encompassing dose for SFRS was 24 Gy (range: 17-26) compared to 45 Gy (range: 20-60) in 2-12 fractions with fSBRT. The median follow-up time was 21 months (range: 3-68). LC rates at 1 and 2 years for SFSR vs. fSBRT were 89 and 83% vs. 75 and 59%, respectively (p = 0.026). LM treated with SFSR were significantly smaller (p = 0.001). The 1 and 2-year OS rates for all patients were 84 and 71%, respectively. In univariate analysis treatment with SFRS, an interval of ≥12 months between diagnosis of LM and treatment, non-colorectal cancer histology and BED < 100 Gy were significantly associated with better LC. However, none of these parameters remained significant in the multivariate Cox regression model. OS was significantly better in patients with negative lymph nodes (N0), Karnofsky performance status (KPS) > 70% and time to first metastasis ≥12 months. There was no grade 3 acute or late toxicity.

Conclusions: Longer time to first metastasis, good KPS and N0 predicted better OS. Good LC and low toxicity rates were achieved after short SBRT schedules.

Alzheimer’s disease and small vessel ischemic disease frequently co-exist in the aging brain. However, pathogenic links between these 2 disorders are yet to be identified. Therefore we used Taqman genotyping, exome and RNA sequencing to investigate Alzheimer’s disease known pathogenic variants and pathways: APOE ε4 allele, APP-Aβ metabolism and late-onset Alzheimer’s disease main genome-wide association loci (APOE, BIN1, CD33, MS4A6A, CD2AP, PICALM, CLU, CR1, EPHA1, ABCA7) in 96 early-onset small vessel ischemic disease Caucasian patients and 368 elderly neuropathologically proven controls (HEX database) and in a mouse model of cerebral hypoperfusion. Only a minority of patients (29%) carried APOE ε4 allele. We did not detect any pathogenic mutation in APP, PSEN1 and PSEN2 and report a burden of truncating mutations in APP-Aß degradation genes. The single-variant association test identified 3 common variants with a likely protective effect on small vessel ischemic disease (0.54>OR > 0.32, adj. p-value <0.05) (EPHA1 p.M900V and p.V160A and CD33 p.A14V). Moreover, 5/17 APP-Aß catabolism genes were significantly upregulated (LogFC > 1, adj. p-val<0.05) together with Apoe, Ms4a cluster and Cd33 during brain hypoperfusion and their overexpression correlated with the ischemic lesion size. Finally, the detection of Aβ oligomers in the hypoperfused hippocampus supported the link between brain ischemia and Alzheimer’s disease pathology.

Sulfur belongs among H2O, CO2, and Cl as one of the key volatiles in Earth’s chemical cycles. High oxygen fugacity, sulfur concentration, and δ34S values in volcanic arc rocks have been attributed to significant sulfate addition by slab fluids. However, sulfur speciation, flux, and isotope composition in slab-dehydrated fluids remain unclear. Here, we use high-pressure rocks and enclosed veins to provide direct constraints on subduction zone sulfur recycling for a typical oceanic lithosphere. Textural and thermodynamic evidence indicates the predominance of reduced sulfur species in slab fluids; those derived from metasediments, altered oceanic crust, and serpentinite have δ34S values of approximately −8‰, −1‰, and +8‰, respectively. Mass-balance calculations demonstrate that 6.4% (up to 20% maximum) of total subducted sulfur is released between 30–230 km depth, and the predominant sulfur loss takes place at 70–100 km with a net δ34S composition of −2.5 ± 3‰. We conclude that modest slab-to-wedge sulfur transport occurs, but that slab-derived fluids provide negligible sulfate to oxidize the sub-arc mantle and cannot deliver 34S-enriched sulfur to produce the positive δ34S signature in arc settings. Most sulfur has negative δ34S and is subducted into the deep mantle, which could cause a long-term increase in the δ34S of Earth surface reservoirs.

Spin thermo-electric phenomena have attracted wide attention recently, e.g., the spin Peltier effect—heat generation by magnonic spin currents. Here, we find that the spin Peltier effect also manifests as a heat wave accompanying fast moving magnetic textures. High speed and extreme magnetic excitation localisation are paramount for efficient transfer of energy from the spin-degrees of freedom to electrons and lattice. While satisfying both conditions is subject to severe restrictions in ferromagnets, we find that domain walls in antiferromagnets can overcome these limitations due to their ultrahigh mobility and ultra-small widths originating from the relativistic contraction. To illustrate our findings, we show that electric current driven domain wall motion in the antiferromagnetic metal Mn2Au can carry a localised heat wave with temperature up to 1 K. Since domain walls are localised magnetic objects, this effect has the potential for nanoscale heating sensing and functionalities.

FGF2 is a tumor cell survival factor that is exported from cells by an ER/Golgi-independent secretory pathway. This unconventional mechanism of protein secretion is based on direct translocation of FGF2 across the plasma membrane. The Na,K-ATPase has previously been shown to play a role in this process, however, the underlying mechanism has remained elusive. Here, we define structural elements that are critical for a direct physical interaction between FGF2 and the α1 subunit of the Na,K-ATPase. In intact cells, corresponding FGF2 mutant forms were impaired regarding both recruitment at the inner plasma membrane leaflet and secretion. Ouabain, a drug that inhibits both the Na,K-ATPase and FGF2 secretion, was found to impair the interaction of FGF2 with the Na,K-ATPase in cells. Our findings reveal the Na,K-ATPase as the initial recruitment factor for FGF2 at the inner plasma membrane leaflet being required for efficient membrane translocation of FGF2 to cell surfaces.

During poultry slaughter and processing, microbial cross-contamination between individual chickens is possible, as well as from one slaughter animal to the next without direct contact. One option for reducing the risk of cross-contamination is to decrease the number of microorganisms on contact surfaces by using disinfectants. The aim is to decontaminate the surfaces coming into direct contact with the carcasses. In the present study, the effectiveness of different disinfectants was investigated in laboratory settings, simulating the conditions in the slaughterhouses and in a chicken slaughterhouse. For this, an artificial residue substance (consisting of yeast extract, albumin, and agar) was developed, tested, and included in the assays. Two disinfectants were tested under laboratory conditions: lactic acid (5 and 6.67%) and peracetic acid (0.33 and 0.5%). At the slaughterhouse, peracetic acid (0.021%) was used. In the laboratory tests, it was found that the peracetic acid solution had the highest disinfection potential with respect to an Escherichia coli strain (reduction >4 log CFU mL−1) at 0.5% without an artificial residue substance. The tested lactic acid solutions also showed the highest disinfection potential against a Pseudomonas aeruginosa strain, without an artificial residue substance. When applying the artificial residue substance, the reduction potential of lactic acid and peracetic acid was decreased to less than 1.4 log CFU mL−1. Application of peracetic acid in the slaughterhouse reduced the number of total aerobic bacteria by more than 4 log CFU mL−1 and the number of Enterobacteriaceae by more than 3 log CFU mL−1, depending on the place of sampling.

Background: Cholinergic urticaria (CholU) is a common type of chronic inducible urticaria, characterized by small itchy wheals that appear upon physical exercise or passive warming. Malassezia globosa, a skin resident fungus, has been identified as an antigen that induces mast cell/basophil degranulation and wheal formation through specific IgE, in Japanese patients with atopic dermatitis and CholU. In this study we aimed in assessing the rate of IgE sensitizations against skin resident fungi in European CholU patients.

Methods: We assessed serum IgE levels to Malassezia furfur, Candida albicans and Trichophyton mentagrophytes using routine lab testing and Malassezia globosa using a newly established ELISA. We correlated the results to wheal formation and other clinical features.

Results: Four patients (of 30 tested) had elevated levels of IgE against Malassezia furfur and Candida albicans and two had elevated levels of IgE against Trichophyton mentagrophytes. Four sera (of 25 tested) had elevated levels of IgE to the Malassezia globosa antigen supMGL_1304. Sensitization to one skin fungus was highly correlated with sensitization to the other tested fungi. We saw highly significant correlations of sensitization to supMGL_1304 with wheal size in the autologous sweat skin test (rs = 0.7, P = 0.002, n = 19), the Erlangen atopy score (rs = 0.5, P = 0.03, n = 19), total IgE serum levels (rs = 0.5, P = 0.04, n = 19) and a positive screen for IgE against common airborne/inhalant allergens s (sx1; rs = 0.54, P = 0.02, n = 19).

Conclusions: Sensitization to skin resident fungi including Malassezia globosa is uncommon in European CholU patients, but is associated with atopy and pronounced wheal formation upon dermal contact with their own sweat.Trial registration German Clinical Trials Registry DRKS-ID: DRKS00004277.

The present article deals with two key drivers of social acceptance of wind energy: procedural justice and distributional justice. It is based on a comparative expert assessment carried out in the frame of the Horizon 2020 project WinWind covering six European countries. The focus of the paper is on procedural and financial participation of citizens and local stakeholders in wind energy projects. The first part covers institutional arrangements for public engagement in two areas of the decision-making process—wind turbine zoning/siting in spatial plans and authorization procedures. Here, three levels of public involvement—information, consultation and participation—were analyzed. The second part examines active and financial participation of citizens and local stakeholders. Here, we distinguish between two different modes of governance: institutionalized forms of public governance and voluntary forms of corporate governance. The outcomes suggest that concrete paths to the social acceptance of wind energy are fostered via appropriate institutional spaces for public engagement. Furthermore, missing opportunities for active and passive financial participation can have strong negative consequences for community acceptance.

Background: Access to a bank account is critical for overall participation in social life and an indicator for social integration. Worldwide about 1.7 billion people remain with no access to banking facilities as a form of financial exclusion which represents 31% of the world's general population. In contrast, in Western countries like Germany, 99% of the general population use bank accounts.

Methods: We conducted an exploratory cross-sectional survey on bank account ownership and bank account access among psychiatric in-patients in a psychiatric hospital in Berlin. Out of 540 participants who were reached for an interview, 486 shared information about bank account ownership and 469 on access.

Results: Out of 486 participants 49 (10.1%) did not own a bank account. Among the remaining 420 participants owning a bank account, 36 (8.3%) did not have direct access to their bank account, but only, e.g., their legal guardian. Regression results found psychosis, intellectual disabilities, a longer treatment duration, as well as being of male gender and a more instable housing status to be significantly associated with a missing bank account or a missing access to one's bank account.

Conclusions: The lack of bank account ownership and access among this population of psychiatric patients is concerning. The interrelationship between factors of financial exclusion and mental health should be further explored in longitudinal studies. More attention is needed to support people with severe mental illness to be able to access resources associated with financial inclusion.

Members of different virus families including Hantaviridae cause viral hemorrhagic fevers (VHFs). The decisive determinants of hantavirus-associated pathogenicity are still enigmatic. Pathogenic hantavirus species, such as Puumala virus (PUUV), Hantaan virus (HTNV), Dobrava-Belgrade virus (DOBV), and Sin Nombre virus (SNV), are associated with significant case fatality rates. In contrast, Tula virus (TULV) only sporadically causes mild disease in immunocompetent humans and Prospect Hill virus (PHV) so far has not been associated with any symptoms. They are thus defined here as low pathogenic/apathogenic hantavirus species. We found that productive infection of cells of the mononuclear phagocyte system (MPS), such as monocytes and dendritic cells (DCs), correlated well with the pathogenicity of hantavirus species tested. HTNV (intermediate case fatality rates) replicated more efficiently than PUUV (low case fatality rates) in myeloid cells, whereas low pathogenic/apathogenic hantavirus species did not produce any detectable virus titers. Analysis of PHPUV, a reassortant hantavirus derived from a pathogenic (PUUV) and an apathogenic (PHV) hantavirus species, indicated that the viral glycoproteins are not decisive for replication in MPS cells. Moreover, blocking acidification of endosomes with chloroquine decreased the number of TULV genomes in myeloid cells suggesting a post-entry block for low pathogenic/apathogenic hantavirus species in myeloid cells. Intriguingly, pathogenic but not low pathogenic/apathogenic hantavirus species induced conversion of monocytes into inflammatory DCs. The proinflammatory programming of MPS cells by pathogenic hantavirus species required integrin signaling and viral replication. Our findings indicate that the capacity to replicate in MPS cells is a prominent feature of hantaviral pathogenicity.