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Medical education has a long tradition of using various patient representations in teaching and assessment. With this literature review we aim, first, to provide an overview of the most important patient representations used to teach and assess clinical skills, considering in particular “summative exams” that have a pass or fail outcome; second, to provide arguments for choosing certain patient representations; and third, to show the advantages and limitations of different patient representations, especially simulated patients (SPs) and real patients (RPs). Typical patient representations include case narratives, anatomical models, simulators and mannequins, as well as SPs and RPs. The literature indicates that there are multiple ways of using various patient representations in teaching and that the intended didactical purpose informs the choice of representation. Early in the educational programme, even low-fidelity patient representations can be a good fit for assessment purposes if chosen to match the educational level. The use of RPs in summative, high-stakes assessments (exams with particularly important consequences for the examinee) is limited for methodological and ethical reasons. The methodological implementation of summative exams also entails specific challenges, such as ensuring measurement reliability and fairness towards the examinees. Carefully prepared, SPs can perform their roles with a sufficient degree of authenticity, making summative exams more manageable, and imposing no strain or risk on RPs. The ongoing debate concerning the use of SPs and RPs in summative assessment highlights perceived limitations of SPs in relation to RPs that are often not supported by research. Evidence shows that SPs, in combination with additional simulation modalities as needed, represent the first choice for summative clinical assessment. We also consider the strengths and limitations of this review and reflect on the applicability of our findings. We conclude that in order to select the right patient representations in clinical teaching and/or assessment, a number of perspectives must be considered: (i) the learning goals, aligned with the stage of study, (ii) the corresponding requirements of the clinical task itself (e.g., performing a phlebotomy or a communication task), (iii) the level of authenticity required and (iv) the resources needed, taking patient safety and feasibility into consideration.

Diesel oil contamination is a growing environmental concern in most crude oil processing regions of the world. This study assessed the efficacy of both fresh and powdered Eichhornia crassipes (water hyacinth) as potential biostimulants in the remediation of diesel oil contaminated soils using three test concentrations (50 g, 100 g and 150 g) and a control (0 g). The remediation process was monitored by assaying the total organic carbon (TOC), total petroleum hydrocarbon (TPH), and soil pH before and after amendment with the fresh and powdered E. crassipes for 90 days. The result showed increase in soil pH, TOC, TPH and volatile matter (VM) in comparison with the control due to soil contamination by diesel oil. However, there was a significant reduction (p < 0.05) in soil pH and TOC with the introduction of fresh and powdered E. crassipes at different concentrations. Contaminated soil amended with 100 g of fresh E. crassipes showed the highest TOC loss (59.7%) alongside soil amended with 100 g of powdered E. crassipes (47.36%) while the control showed the least TOC loss (0.91%). Similarly, soil TPH decreased significantly across all concentrations after amendment (p < 0.05). Overall, soil amended with fresh E. crassipes showed higher TPH loss than soil amended with powdered E. crassipes. This study reveals the potentials of using E. crassipes in the remediation of diesel oil contaminated soils. Above all, we demonstrate that fresh E. crassipes is a potentially stronger biostimulant than powdered E. crassipes.

Gliomas are the most frequent primary tumors of the brain. They can be divided into grade II-IV astrocytomas and grade II-III oligodendrogliomas, based on their histomolecular profile. The prognosis and treatment is highly dependent on grade and well-identified prognostic and/or predictive molecular markers. Multi-parametric MRI, including diffusion weighted imaging, perfusion, and MR spectroscopy, showed increasing value in the non-invasive characterization of specific molecular subsets of gliomas. Radiolabeled amino-acid analogues, such as 18F-FET, have also been proven valuable in glioma imaging. These tracers not only contribute in the diagnostic process by detecting areas of dedifferentiation in diffuse gliomas, but this technique is also valuable in the follow-up of gliomas, as it can differentiate pseudo-progression from real tumor progression. Since multi-parametric MRI and 18F-FET PET are complementary imaging techniques, there may be a synergistic role for PET-MRI imaging in the neuro-oncological imaging of primary brain tumors. This could be of value for both primary staging, as well as during treatment and follow-up.

Scanning electrochemical microscopy (SECM) used in the feedback mode is one of the most powerful versatile analytical tools used in the field of battery research. However, the application of SECM in the field of lithium-ion batteries (LIBs) faces challenges associated with the selection of a suitable redox mediator due to its high reactivity at low potentials at lithium metal or lithiated graphite electrodes. In this regard, the electrochemical/chemical stability of 2,5-di-tert-butyl-1,4-dimethoxybenzene (DBDMB) is evaluated and benchmarked with ferrocene. This investigation is systematically carried out in both linear and cyclic carbonates of the electrolyte recipe. Measurements of the bulk current with a microelectrode prove that while DBDMB decomposes in ethyl methyl carbonate (EMC)-containing electrolyte, bulk current remains stable in cyclic carbonates, ethylene carbonate (EC) and propylene carbonate (PC). Ferrocene was studied as an alternative redox mediator, showing superior electrochemical performance in ethyl methyl carbonate-containing electrolytes in terms of degradation. The resulting robustness of ferrocene with SECM is essential for a quantitative analysis of battery materials over extended periods. SECM approach curves depict practical problems when using the decomposing DBDMB for data acquisition and interpretation. This study sheds light towards the use of SECM as a probing tool enabled by redox mediators.

Introduction The novel coronavirus disease has had significant impact on healthcare globally. Knowledge of this virus is evolving, definitive care is not yet known and mortality is increasing. We assessed its initial impact on paediatric surgical practice in Nigeria, creating a benchmark for recommendations and future reference.Methods Survey of 120 paediatric surgeons from 50 centres to assess sociodemographics and specific domains of impact of COVID-19 on their services and training in Nigeria. Valid responses were represented as categorical data and presented in percentages. Duplicate submissions for centres were excluded by combining and taking the mean of responses from centres with multiple respondents.Results Response rate was 74 (61%). Forty-six (92%) centres had suspended elective surgeries. All centres continued emergency surgeries but volume reduced in March by 31%. Eleven (22%) centres reported 13 suspended elective cases presenting as emergencies in March, accounting for 3% of total emergency surgeries. Twelve (24%) centres adopted new modalities for managing selected surgical conditions: non-operative reduction of intussusception in 1 (2%), antibiotic management of uncomplicated acute appendicitis in 5 (10%) and more conservative management of trauma and replacement of laparoscopic appendectomy with open surgery in 3 (6%), respectively. Low perception of adequacy of personal protective equipment (PPE) was reported in 35 (70%) centres. Forty (80%) centres did not offer telemedicine for patients’ follow-up. Twenty-nine (58%) centres had suspended academic training. Perception of safety to operate was low in 37 (50%) respondents, indifferent in 24% and high in 26%.Conclusion Majority of paediatric surgical centres reported cessation of elective surgeries while continuing emergencies. There was, however, an acute decline in the volume of emergency surgeries. Adequate PPE needs to be provided and preparations towards handling backlog of elective surgeries once the pandemic recedes. Further study is planned to more conclusively understand the full impact of this pandemic on children’s surgery.

Background Adenoviral vectors emerged as important platforms for cancer immunotherapy. Vaccination with adenoviral vectors is promising in this respect, however, their specific mechanisms of action are not fully understood. Here, we assessed the development and maintenance of vaccine-induced tumor-specific CD8+ T cells elicited upon immunization with adenoviral vectors.Methods Adenoviral vaccine vectors encoding the full-length E7 protein from human papilloma virus (HPV) or the immunodominant epitope from E7 were generated, and mice were immunized intravenously with different quantities (107, 108 or 109 infectious units). The magnitude, kinetics and tumor protection capacity of the induced vaccine-specific T cell responses were evaluated.Results The adenoviral vaccines elicited inflationary E7-specific memory CD8+ T cell responses in a dose-dependent manner. The magnitude of these vaccine-specific CD8+ T cells in the circulation related to the development of E7-specific CD8+ tissue-resident memory T (TRM) cells, which were maintained for months in multiple tissues after vaccination. The vaccine-specific CD8+ T cell responses conferred long-term protection against HPV-induced carcinomas in the skin and liver, and this protection required the induction and accumulation of CD8+ TRM cells. Moreover, the formation of CD8+ TRM cells could be enhanced by temporal targeting CD80/CD86 costimulatory interactions via CTLA-4 blockade early after immunization.Conclusions Together, these data show that adenoviral vector-induced CD8+ T cell inflation promotes protective TRM cell populations, and this can be enhanced by targeting CTLA-4.

Microorganisms perform countless tasks on Earth and they are expected to be essential for human space exploration. Despite the interest in the responses of bacteria to space conditions, the findings on the effects of microgravity have been contradictory, while the effects of Martian gravity are nearly unknown. We performed the ESA BioRock experiment on the International Space Station to study microbe-mineral interactions in microgravity, simulated Mars gravity and simulated Earth gravity, as well as in ground gravity controls, with three bacterial species: Sphingomonas desiccabilis, Bacillus subtilis, and Cupriavidus metallidurans. To our knowledge, this was the first experiment to study simulated Martian gravity on bacteria using a space platform. Here, we tested the hypothesis that different gravity regimens can influence the final cell concentrations achieved after a multi-week period in space. Despite the different sedimentation rates predicted, we found no significant differences in final cell counts and optical densities between the three gravity regimens on the ISS. This suggests that possible gravity-related effects on bacterial growth were overcome by the end of the experiment. The results indicate that microbial-supported bioproduction and life support systems can be effectively performed in space (e.g., Mars), as on Earth.

Background As a response to the COVID-19 pandemic, most countries have adopted measures of social distance, with the childhood population being one of the main focus of attention in these measures.Methods A rapid scoping review was carried out by searching PubMed to know if children are more contagious than adults, and the proportion of asymptomatic cases in children. Google Scholar and MedRxiv/bioRxiv were also searched. The time period was restricted from 1 December 2019 until 28 May 2020. Only studies published in English, Italian, French or Spanish were included.Results Fourteen out of 1099 identified articles were finally included. Studies included cases from China (n=9 to 2143), China and Taiwan (n=536), Korea (n=1), Vietnam (n=1), Australia (n=9), Geneva (n=40), the Netherlands (n=116), Ireland (n=3) and Spain (population-based study of IgG, n=8243). Although no complete data were available, between 15% and 55%–60% were asymptomatic, and 75%–100% of cases were from family transmission. Studies analysing school transmission showed children as not a driver of transmission. Prevalence of COVID-19 IgG antibody in children

The memory CD8 T-cell pool must select for clones that bind immunodominant epitopes with high affinity to efficiently counter reinfection. At the same time, it must retain a level of clonal diversity to allow recognition of pathogens with mutated epitopes. How the level of diversity within the memory pool is controlled is unclear, especially in the context of a selective drive for antigen affinity. We find that preservation of clones that bind the activating antigen with low affinity depends on expression of the transcription factor Eomes in the first days after antigen encounter. Eomes is induced at low activating signal strength and directly drives transcription of the prosurvival protein Bcl-2. At higher signal intensity, T-bet is induced which suppresses Bcl-2 and causes a relative survival advantage for cells of low affinity. Clones activated with high-affinity antigen form memory largely independent of Eomes and have a proliferative advantage over clones that bind the same antigen with low affinity. This causes high-affinity clones to prevail in the memory pool, despite their relative survival deficit. Genetic or therapeutic targeting of the Eomes/Bcl-2 axis reduces the clonal diversity of the memory pool, which diminishes its ability to respond to pathogens carrying mutations in immunodominant epitopes. Thus, we demonstrate on a molecular level how sufficient diversity of the memory pool is established in an environment of affinity-based selection.

The rising incidence of multidrug resistance in Gram-negative bacteria underlines the urgency for novel treatment options. One promising new approach is the synergistic combination of antibiotics with antimicrobial peptides. However, the use of such peptides is not straightforward; they are often sensitive to proteolytic degradation, which greatly limits their clinical potential. One approach to increase stability is to apply a hydrocarbon staple to the antimicrobial peptide, thereby fixing them in an α-helical conformation, which renders them less exposed to proteolytic activity. In this work we applied several different hydrocarbon staples to two previously described peptides shown to act on the outer membrane, L6 and L8, and tested their activity in a zebrafish embryo infection model using a clinical isolate of Acinetobacter baumannii as a pathogen. We show that the introduction of such a hydrocarbon staple to the peptide L8 improves its in vivo potentiating activity on antibiotic treatment, without increasing its in vivo antimicrobial activity, toxicity or hemolytic activity.

Background: Systemic inflammation can occur after transcatheter aortic valve replacement (TAVR) and correlates with adverse outcome. The impact of remote ischemic preconditioning (RIPC) on TAVR associated systemic inflammation is unknown and was focus of this study. Methods: We performed a prospective controlled trial at a single center and included 66 patients treated with remote ischemic preconditioning (RIPC) prior to TAVR, who were matched to a control group by propensity score. RIPC was applied to the upper extremity using a conventional tourniquet. Definition of systemic inflammation was based on leucocyte count, C-reactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6), assessed in the first 5 days following the TAVR procedure. Mortality was determined within 6 months after TAVR. RIPC group and matched control group showed comparable baseline characteristics. Results: Systemic inflammation occurred in 66% of all patients after TAVR. Overall, survival after 6 months was significantly reduced in patients with systemic inflammation. RIPC, in comparison to control, did not significantly alter the plasma levels of leucocyte count, CRP, PCT or IL-6 within the first 5 days after TAVR. Furthermore, inflammation associated survival after 6 months was not improved by RIPC. Of all peri-interventional variables assessed, only the amount of the applied contrast agent was connected to the occurrence of systemic inflammation. Conclusions: Systemic inflammation frequently occurs after TAVR and leads to increased mortality after 6 months. RIPC neither reduces the incidence of systemic inflammation nor improves inflammation associated patient survival within 6 months.

Abstract We present a detailed and self-contained analysis of the universal SchwingerKeldysh effective field theory which describes macroscopic thermal fluctuations of a relativistic field theory, elaborating on our earlier construction [1]. We write an effective action for appropriate hydrodynamic Goldstone modes and fluctuation fields, and discuss the symmetries to be imposed. The constraints imposed by fluctuation-dissipation theorem are manifest in our formalism. Consequently, the action reproduces hydrodynamic constitutive relations consistent with the local second law at all orders in the derivative expansion, and captures the essential elements of the eightfold classification of hydrodynamic transport of [2]. We demonstrate how to recover the hydrodynamic entropy and give predictions for the non-Gaussian hydrodynamic fluctuations. The basic ingredients of our construction involve (i) doubling of degrees of freedom a la Schwinger-Keldysh, (ii) an emergent gauge U(1)T symmetry associated with entropy which is encapsulated in a Noether current a la Wald, and (iii) a BRST/topological supersymmetry imposing the fluctuation-dissipation theorem a la Parisi-Sourlas. The overarching mathematical framework for our construction is provided by the balanced equivariant cohomology of thermal translations, which captures the basic constraints arising from the Schwinger-Keldysh doubling, and the thermal Kubo-Martin-Schwinger relations. All these features are conveniently implemented in a covariant superspace formalism. An added benefit is that the second law can be understood as being due to entropy inflow from the Grassmann-odd directions of superspace.

Abstract We derive an effective field theory for general chaotic two-dimensional conformal field theories with a large central charge. The theory is a specific and calculable instance of a more general framework recently proposed in [1]. We discuss the gauge symmetries of the model and how they relate to the Lyapunov behaviour of certain correlators. We calculate the out-of-time-ordered correlators diagnosing quantum chaos, as well as certain more fine-grained higher-point generalizations, using our Lorentzian effective field theory. We comment on potential future applications of the effective theory to real-time thermal physics and conformal field theory.

Abstract Small randomized trials have not shown an overall survival (OS) difference among local treatment modalities for patients with extremity soft‐tissue sarcomas (E‐STS) but were underpowered for OS. We examine the impact of local treatment modalities on OS and sarcoma mortality (SM) using two national registries. The National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) Program were analyzed separately to identify patients with stage II‐III, high‐grade E‐STS diagnosed between 2004 and 2013 and treated with (1) amputation alone, (2) limb‐sparing surgery (LSS) alone, (3) preoperative radiation therapy (RT) and LSS, or (4) LSS and postoperative RT. Multivariable analyses (MVAs) and 1:1 matched pair analyses (MPAs) examined treatment impacts on OS (both databases) and SM (SEER only). From the NCDB and SEER, 7828 and 2937 patients were included. On MVAs, amputation was associated with inferior OS and SM. Relative to LSS alone, both preoperative RT and LSS (HR, 0.70; 95% CI: 0.62‐0.78) and LSS and postoperative RT (HR, 0.69; 95% CI: 0.63‐0.75) improved OS in NCDB analyses with confirmation by SEER. Estimated median survivals from MPA utilizing NCDB data were 7.2 years with LSS alone (95% CI: 6.5‐8.9 years) vs 9.8 years (95% CI: 9.0‐11.2 years) with LSS and postoperative RT. A MPA comparing preoperative RT and LSS to LSS alone found median survivals of 8.9 years (95% CI: 7.9‐not estimable) and 6.6 years (95% CI: 5.4‐7.8 years). Optimal high‐grade E‐STS management includes LSS with preoperative or postoperative RT as evidenced by superior OS and SM.

La electro-movilidad polariza. Si bien la industria automotriz, los gobiernos y muchos medios de comunicación asignan a la movilidad eléctrica un importante rol en la lucha contra el cambio climático y la contaminación atmosférica, la producción de baterías de alto rendimiento también va acompañada de una creciente demanda de materias primas estratégicas, incluido el litio. En el siguiente artículo, presentamos en primer lugar aspectos importantes de la transformación actual de la industria automotriz en Alemania. A continuación, describimos los problemas de las materias primas de la electro-movilidad utilizando el ejemplo de la minería del litio en América del Sur. Sobre la base de una estadía de campo de diez meses en la región, realizada entre 2018 y 2019, presentamos los problemas especiales de la minería del litio en los Salares altoandinos de América del Sur. Las investigaciones se centraron principalmente en métodos de investigación social cualitativa.

Abstract The short- and long-term success of intravascular stents depends on a proper re-endothelialisation after the intervention-induced endothelial denudation. The aim of this study was to evaluate the potential of in vivo molecular imaging of glutamate carboxypeptidase II (GCPII; identical with prostate-specific membrane antigen PSMA) expression as a marker of re-endothelialisation. Fifteen Sprague Dawley rats underwent unilateral balloon angioplasty of the common carotid artery (CCA). Positron emission tomography (PET) using the GCPII-targeting tracer [18F]DCFPyL was performed after 5–21 days (scan 60–120 min post injection). In two animals, the GCPII inhibitor PMPA (23 mg/kg BW) was added to the tracer solution. After PET, both CCAs were removed, dissected, and immunostained with the GCPII specific antibody YPSMA-1. Difference of GCPII expression between both CCAs was established by PCR analysis. [18F]DCFPyL uptake was significantly higher in the ipsilateral compared to the contralateral CCA with an ipsi-/contralateral ratio of 1.67 ± 0.39. PMPA blocked tracer binding. The selective expression of GCPII in endothelial cells of the treated CCA was confirmed by immunohistological staining. PCR analysis verified the site-specific GCPII expression. By using a molecular imaging marker of GCPII expression, we provide the first non-invasive in vivo delineation of re-endothelialisation after angioplasty.

The theoretical capabilities and practical recommendations of increasing the both an accuracy of coordinate estimation and reliability of ballistic and space targets classification by using estimates of range higher order derivatives for surveillance object in early warning radars (EWR) were studied in previous papers of the authors. Nevertheless, the recommendations were not considered as to practical design selection for the algorithm of refinement angular velocity of targets under the criterion of maximum accuracy of target coordinates estimation. Therefore, the article deals with the methodology of comparative evaluation accuracy characteristics of algorithms of refinement angular velocity ballistic and space objects and assessing the level of their improvement through the use of different variants of construction algorithm of increasing the accuracy of range higher order derivatives, including information on the third derivative of distance. By the results of modeling conclusions about choosing the best options for handling data depending on the context and the input

Atrial fibrillation (AF) is well known for being a major risk factor of thromboembolic stroke. We could recently demonstrate an association of monocyte–platelet aggregates (MPAs) with the degree of thrombogenicity in patients with AF. This study investigated platelet activation markers, as potential biomarkers for the presence of left atrial (LA) thrombus in patients with AF. One hundred and eight patients with symptomatic AF underwent transesophageal echocardiography (TEE) before scheduled cardioversion or pulmonary vein isolation. In order to determine the content of MPAs by flow-cytometric quantification analyses, blood was drawn on the day of TEE. The soluble CD40 Ligand (sCD40L) and soluble P-selectin (sP-selectin) were obtained by Cytometric Bead Arrays (CBA). D-dimer levels were detected by quantitative immunological determination of fibrin degradation products. Clinical, laboratory, and echocardiographic standard parameters were obtained from all patients, including the determination of the flow in the left atrial appendage (LAA). Patients with detected LA thrombus (n = 28) compared with patients without thrombus (n = 80) showed an increased number of common risk factors, such as age, diabetes, heart failure, and coronary artery disease (CAD). The presence of LA thrombus was associated with significantly increased levels of MPAs (147 ± 12 vs. 304 ± 29 per µl; p < 0.00), sCD40L (106.3 ± 31.0 vs. 33.5 ± 2.1 pg/ml, p = 0.027), and D-dimer (0.13 ± 0.02 vs. 0.69 ± 0.21 mg FEU/l, p = 0.015). In contrast, sP-selectin showed no association with LA thrombus. A multivariate regression analysis showed that MPAs, sCD40L as well as D-dimers were independent indicators for the existence of LA thrombus. MPAs above 170 cells/µl indicated LA thrombus with a high sensitivity of 93% and a specificity of 73% (OR 62, 95% CI. 6.9–557.2, p < 0.001) in patients with AF, whereas the D-dimer lost their quality as independent indicator by using the conventional cut-off of 0.5 mg/l within the regression analysis. MPAs, as well as the D-dimer, correlated significantly negatively with the flow in the LAA measured during TEE. The content of MPAs, sCD40L, and D-dimer, but not sP-selectin showed an increased dependence on LA thrombus in patients with AF. In our study group, MPAs showed the best diagnostic test accuracy of the compared platelet markers. The different results of the examined platelet activation markers could be an indication of diverse mechanisms of LA thrombus in AF. Further studies should evaluate whether determination of MPAs in clinical routine may suffice to indicate the presence of LA thrombus in patients with AF.

Abstract Background Wilson’s disease is an inherited autosomal recessive multi-systemic disorder characterized by reduced excretion and consequently excessive accumulation of copper in different organs, such as the heart. Results In a prospective controlled trial, which is the largest to date, we evaluated 61 patients with Wilson’s disease, age- and sex-matched to 61 healthy patients, for cardiac manifestation using cardiac magnetic resonance imaging. Patients were under stable disease and had no signs of heart failure at the time of examination. We detected a left ventricular cleft, an invagination penetrating more than 50% wall thickness of the adjoining compact myocardium in diastole, in 20% of the patients (12 out of 61) compared to 5% among control patients (3 out of 61, p = 0.013). No correlation between the incidence of cleft and a certain genotype of Wilson’s disease was found. All described cases were incidental findings and none of the patients showed other signs of cardiac involvement. Conclusions To conclude, the results of this study suggests that the increased occurrence of left ventricular clefts is due to Wilson’s disease. Large studies with a long observation period are needed for further evaluation.

Summary: α-Actinins, a family of critical cytoskeletal actin-binding proteins that usually exist as anti-parallel dimers, play crucial roles in organizing the framework of the cytoskeleton through crosslinking the actin filaments, as well as in focal adhesion maturation. However, the molecular mechanisms underlying its functions are unclear. Here, by mechanical manipulation of single human α-actinin 1 using magnetic tweezers, we determined the mechanical stability and kinetics of the functional domains in α-actinin 1. Moreover, we identified the force-dependence of vinculin binding to α-actinin 1, with the demonstration that force is required to expose the high-affinity binding site for vinculin binding. Further, a role of the α-actinin 1 as molecular shock absorber for the cytoskeleton network is revealed. Our results provide a comprehensive analysis of the force-dependent stability and interactions of α-actinin 1, which sheds important light on the molecular mechanisms underlying its mechanotransmission and mechanosensing functions. : α-Actinins are critical actin crosslinking proteins that organize actin cytoskeletal networks. Le et al. determine the mechanical stability and dynamics of human α-actinin 1 and the force-dependence of vinculin binding to α-actinin 1, which sheds light on the molecular mechanisms of mechanotransmission and mechanosensing. Keywords: α-actinin 1, cytoskeleton, mechanosensing, mechanostransmission, vinculin binding, magnetic tweezers, single molecule manipulation, molecular shock absorber

Abstract We describe general features of thermal correlation functions in quantum systems, with specific focus on the fluctuation-dissipation type relations implied by the KMS condition. These end up relating correlation functions with different time ordering and thus should naturally be viewed in the larger context of out-of-time-ordered (OTO) observables. In particular, eschewing the standard formulation of KMS relations where thermal periodicity is combined with time-reversal to stay within the purview of Schwinger-Keldysh functional integrals, we show that there is a natural way to phrase them directly in terms of OTO correlators. We use these observations to construct a natural causal basis for thermal n-point functions in terms of fully nested commutators. We provide several general results which can be inferred from cyclic orbits of permutations, and exemplify the abstract results using a quantum oscillator as an explicit example.

Sickness behavior is the common denominator for a plethora of changes in normal behavioral routines and systemic metabolism during an infection. Typical symptoms include temperature, muscle weakness, and loss of appetite. Whereas we experience these changes as a pathology, in fact they are a carefully orchestrated response mediated by the immune system. Its purpose is to optimize immune cell functionality against pathogens whilst minimizing viral replication in infected cells. Sickness behavior is controlled at several levels, most notably by the central nervous system, but also by other organs that mediate systemic homeostasis, such as the liver and adipose tissue. Nevertheless, the changes mediated by these organs are ultimately initiated by immune cells, usually through local or systemic secretion of cytokines. The nature of infection determines which cytokine profile is induced by immune cells and therefore which sickness behavior ensues. In context of infection, sickness behavior is typically beneficial. However, inappropriate activation of the immune system may induce adverse aspects of sickness behavior. For example, tissue stress caused by obesity may result in chronic activation of the immune system, leading to lasting changes in systemic metabolism. Concurrently, metabolic disease prevents induction of appropriate sickness behavior following viral infection, thus impairing the normal immune response. In this article, we will revisit recent literature that elucidates both the benefits and the negative aspects of sickness behavior in context of viral infection.

Over the past 20 years, 68Ga-labelled radiopharmaceuticals have become an important part in clinical routine. However, the worldwide supply with 68Ge/68Ga generators is limited as well as the number of patient doses per batch of 68Ga radiopharmaceutical. In the recent years, a new technique appeared, making use of the ease of aqueous labelling via chelators as with 68Ga but using 18F instead. This technique takes advantage of the strong coordinative bond between aluminium and fluoride, realized in the aqueous cation [Al18F]2+. Most applications to date make use of one-pot syntheses with free Al(III) ions in the system. In contrast, we investigated the labelling approach split into two steps: generating the Al-bearing precursor in pure form and using this Al compound as a precursor in the labelling step with aqueous [18F]fluoride. Hence, no free Al3+ ions are present in the labelling step. We investigated the impact of parameters: temperature, pH, addition of organic solvent, and reaction time using the model chelator NH2-MPAA-NODA. With optimized parameters we could stably achieve a 80% radiochemical yield exerting a 30-min reaction time at 100 °C. This technique has the potential to become an important approach in radiopharmaceutical syntheses.

Abstract Background PET using O-(2-[18F]fluoroethyl)-l-tyrosine (18F-FET) is an established method for brain tumour diagnostics, but data processing varies in different centres. This study analyses the influence of methodological differences between two centres for tumour characterization with 18F-FET PET using the same PET scanner. Methodological differences between centres A and B in the evaluation of 18F-FET PET data were identified for (1) framing of PET dynamic data, (2) data reconstruction, (3) cut-off values for tumour delineation to determine tumour-to-brain ratios (TBR) and tumour volume (Tvol) and (4) ROI definition to determine time activity curves (TACs) in the tumour. Based on the 18F-FET PET data of 40 patients with untreated cerebral gliomas (20 WHO grade II, 10 WHO grade III, 10 WHO grade IV), the effect of different data processing in the two centres on TBRmean, TBRmax, Tvol, time-to-peak (TTP) and slope of the TAC was compared. Further, the effect on tumour grading was evaluated by ROC analysis. Results Significant differences between centres A and B were found especially for TBRmax (2.84 ± 0.99 versus 3.34 ± 1.13; p

Abstract In this paper, we demonstrate the emergence of nonlinear gravitational equations directly from the physics of a broad class of conformal field theories. We consider CFT excited states defined by adding sources for scalar primary or stress tensor operators to the Euclidean path integral defining the vacuum state. For these states, we show that up to second order in the sources, the entanglement entropy for all ball-shaped regions can always be represented geometrically (via the Ryu-Takayanagi formula) by an asymptotically AdS geometry. We show that such a geometry necessarily satisfies Einstein’s equations perturbatively up to second order, with a stress energy tensor arising from matter fields associated with the sourced primary operators. We make no assumptions about AdS/CFT duality, so our work serves as both a consistency check for the AdS/CFT correspondence and a direct demonstration that spacetime and gravitational physics can emerge from the description of entanglement in conformal field theories.

Abstract Causally ordered correlation functions of local operators in near-thermal quantum systems computed using the Schwinger-Keldysh formalism obey a set of Ward identities. These can be understood rather simply as the consequence of a topological (BRST) algebra, called the universal Schwinger-Keldysh superalgebra, as explained in our compan-ion paper [1]. In the present paper we provide a mathematical discussion of this topological algebra. In particular, we argue that the structures can be understood in the language of extended equivariant cohomology. To keep the discussion self-contained, we provide a ba-sic review of the algebraic construction of equivariant cohomology and explain how it can be understood in familiar terms as a superspace gauge algebra. We demonstrate how the Schwinger-Keldysh construction can be succinctly encoded in terms a thermal equivariant cohomology algebra which naturally acts on the operator (super)-algebra of the quantum system. The main rationale behind this exploration is to extract symmetry statements which are robust under renormalization group flow and can hence be used to understand low-energy effective field theory of near-thermal physics. To illustrate the general prin-ciples, we focus on Langevin dynamics of a Brownian particle, rephrasing some known results in terms of thermal equivariant cohomology. As described elsewhere, the general framework enables construction of effective actions for dissipative hydrodynamics and could potentially illumine our understanding of black holes.

Abstract We review the Schwinger-Keldysh, or in-in, formalism for studying quantum dynamics of systems out-of-equilibrium. The main motivation is to rephrase well known facts in the subject in a mathematically elegant setting, by exhibiting a set of BRST symmetries inherent in the construction. We show how these fundamental symmetries can be made manifest by working in a superspace formalism. We argue that this rephrasing is extremely efficacious in understanding low energy dynamics following the usual renormalization group approach, for the BRST symmetries are robust under integrating out degrees of freedom. In addition we discuss potential generalizations of the formalism that allow us to compute out-of-time-order correlation functions that have been the focus of recent attention in the context of chaos and scrambling. We also outline a set of problems ranging from stochastic dynamics, hydrodynamics, dynamics of entanglement in QFTs, and the physics of black holes and cosmology, where we believe this framework could play a crucial role in demystifying various confusions. Our companion paper [1] describes in greater detail the mathematical framework embodying the topological symmetries we uncover here.

Atrial fibrillation (AF) is known to cause platelet activation. AF and its degree of thrombogenesis could be associated with monocyte-platelet aggregates (MPAs). We investigated on whether the content of MPAs or other platelet activation markers is associated with the recurrence of AF after pulmonary vein isolation (PVI). A total of 73 patients with symptomatic AF underwent PVI. After 6 months, all patients were evaluated for episodes of AF recurrence. At the same time, flow-cytometric quantification analyses were performed to determine the content of MPAs. Further platelet activation parameters were detected by using either cytometric bead arrays or quantitative immunological determination. Patients with recurrent AF (n = 20) compared to individuals without AF relapse (n = 53) were associated with an increased content of MPAs (43 ± 3% vs. 33 ± 2%, p = 0.004), as well as an increased CD41 expression on monocytes (191 ± 20 vs. 113 ± 6, p = 0.001). The level of the soluble platelet activation markers such as D-dimer, sCD40L, and sP-selectin did not differ between these groups. The content of MPAs correlated weakly with the level of sCD40L (r = 0.26, p = 0.03), but not with sP-selectin and D-dimer, whereas sP-selectin and sCD40L correlated with each other (r = 0.38, p = 0.001). Only the cellular marker of platelet activation, the content of MPAs, was increased in patients with recurrent AF after PVI. In contrast, soluble markers remained unaltered. These data indicate a distinct mechanism and level of platelet activation in AF. The clinical relevance of MPAs in identifying AF recurrence or in guiding the therapy with anticoagulants remains to be elucidated.

Cancer is one of the most frequent and devastating diseases. Previous reports have shown that radio and chemo-resistant cancer stem cell (CSC) population is primarily responsible for cancer recurrences after radiotherapy and chemotherapy. Other studies demonstrated that Lissencephaly-1 (LIS1) protein, also known as platelet activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1), a dynein-binding protein involved in neural stem cell division, plays a crucial role in maintaining CSC population in hematological malignancies. Moreover, one recent report demonstrated that LIS1 gene is preferentially expressed in CD133+ glioblastoma cells and may have also an important role in regulating CD133+ CSC in glioblastoma. The hypothesis of this paper is that LIS1 plays a key role in maintaining CD133+ CSC population in various solid cancers by orientating the cell division plane through an interaction with dynein and therefore controlling the stem cell fate regulatory mechanism. As CD133+ CSC population is responsible for radio- and chemo-resistance, which finally determines the cancer recurrences and metastases, identifying the molecular mechanisms which regulate the CD133+ CSC population represents a major target for cancer research. Given the structure of LIS1, which contains WD40 repeat domain, small peptide inhibitors could be used to alter its function. Therefore, the impact of confirming this hypothesis is significant because LIS1 may become an important molecular target for future adjuvant anticancer therapies directed against radio- and chemo-resistant CSC population.

Clostridioides difficile, a Gram-positive spore-forming bacterium, is the leading cause of nosocomial diarrhea worldwide and therefore a substantial burden to the healthcare system. During the past decade, hypervirulent PCR-ribotypes (RT) e.g., RT027 or RT176 emerged rapidly all over the world, associated with both, increased severity and mortality rates. It is thus of great importance to identify epidemic strains such as RT027 and RT176 as fast as possible. While commonly used diagnostic methods, e.g., multilocus sequence typing (MLST) or PCR-ribotyping, are time-consuming, proteotyping offers a fast, inexpensive, and reliable alternative solution. In this study, we established a MALDI-TOF-based typing scheme for C. difficile. A total of 109 ribotyped strains representative for five MLST clades were analyzed by MALDI-TOF. MLST, based on whole genome sequences, and PCR-ribotyping were used as reference methods. Isoforms of MS-detectable biomarkers, typically ribosomal proteins, were related with the deduced amino acid sequences and added to the C. difficile proteotyping scheme. In total, we were able to associate nine biomarkers with their encoding genes and include them in our proteotyping scheme. The discriminatory capacity of the C. difficile proteotyping scheme was mainly based on isoforms of L28-M (2 main isoforms), L35-M (4 main isoforms), and S20-M (2 main isoforms) giving rise to at least 16 proteotyping-derived types. In our test population, five of these 16 proteotyping-derived types were detected. These five proteotyping-derived types did not correspond exactly to the included five MLST-based C. difficile clades, nevertheless the subtyping depth of both methods was equivalent. Most importantly, proteotyping-derived clade B contained only isolates of the hypervirulent RT027 and RT176. Proteotyping is a stable and easy-to-perform intraspecies typing method and a promising alternative to currently used molecular techniques. It is possible to distinguish the group of RT027 and RT176 isolates from non-RT027/non-RT176 isolates using proteotyping, providing a valuable diagnostic tool.

Background: The fronto-striatal network is involved in various motor, cognitive, and emotional processes, such as spatial attention, working memory, decision-making, and emotion regulation. Intermittent theta burst transcranial magnetic stimulation (iTBS) has been shown to modulate functional connectivity of brain networks. Long stimulation intervals, as well as high stimulation intensities are typically applied in transcranial magnetic stimulation (TMS) therapy for mood disorders. The role of stimulation intensity on network function and homeostasis has not been explored systematically yet.Objective: In this pilot study, we aimed to modulate fronto-striatal connectivity by applying iTBS at different intensities to the left dorso-lateral prefrontal cortex (DLPFC). We measured individual and group changes by comparing resting state functional magnetic resonance imaging (rsfMRI) both pre-iTBS and post-iTBS. Differential effects of individual sub- vs. supra-resting motor-threshold stimulation intensities were assessed.Methods: Sixteen healthy subjects underwent excitatory iTBS at two intensities [90% and 120% of individual resting motor threshold (rMT)] on separate days. Six-hundred pulses (2 s trains, 8 s pauses, duration of 3 min, 20 s) were applied over the left DLPFC. Directly before and 7 min after stimulation, task-free rsfMRI sessions, lasting 10 min each, were conducted. Individual seed-to-seed functional connectivity changes were calculated for 10 fronto-striatal and amygdala regions of interest with the SPM toolbox DPABI.Results: Sub-threshold-iTBS increased functional connectivity directly between the left DLPFC and the left and right caudate, respectively. Supra-threshold stimulation did not change fronto-striatal functional connectivity but increased functional connectivity between the right amygdala and the right caudate.Conclusion: A short iTBS protocol applied at sub-threshold intensities was not only sufficient, but favorable, in order to increase bilateral fronto-striatal functional connectivity, while minimizing side effects. The absence of an increase in functional connectivity after supra-threshold stimulation was possibly caused by network homeostatic effects.

Introduction: Socket prostheses for treatment of distal limb pathology are becoming increasingly prevalent in veterinary medicine, however, limited objective data is available. Objectives of the present study were to retrospectively evaluate owner satisfaction, clinical outcomes, and prognostic factors associated with dogs receiving socket prostheses for partial limbs in a larger patient population.Materials and Methods: Client databases of a single prosthesis provider were reviewed to identify owners whose dogs had received a prosthetic device within the last 10 years. An online survey was developed to evaluate owner-reported outcomes. The survey inquired about anatomy of the residuum, concurrent disease, prosthesis use, rehabilitation, activity, complications, and owner satisfaction. Medical records and radiographs were requested from all participants. Radiographs were used to confirm level of amputation and evaluate for osseous complications. Survey responses were analyzed by assigning author-defined numeric scores defining clinical outcome and owner satisfaction.Results: One-hundred thirty-seven owners were contacted. The response rate was 50/137 (37%); 47 responses were analyzed. Forty-six of 47 owners reported positive satisfaction; 1/47 was displeased. Forty-two of 47 dogs were scored to have acceptable to full function; 5/47 had unacceptable clinical function using the author-defined scoring system. A 62% short-term complication rate and a 19% long-term complication rate were reported. Skin sores were the most common short and long-term complication. There was a significant correlation between both clinical outcome scores and owner satisfaction with days per week spent in the prosthesis. Additionally, clinical outcome scores and owner satisfaction significantly varied between dogs with different durations of prosthesis wear with a trend toward better outcomes associated with longer prosthesis wear. Radiographs were obtained for 23/47 dogs to further define level of defect. The most proximal level of defect was mid-radius for the forelimb and mid-tibia for the hind limb. There was no correlation between level of defect and either owner satisfaction or clinical outcome.Discussion/Conclusion: Results of this survey suggest a high degree of owner satisfaction despite substantial complication rates. Based on preliminary data, further evaluation of socket prostheses as a limb-sparing option for treatment of distal limb pathology should be considered. Prospective clinical trials with objective outcome measures are required to draw firm conclusions.

Tissue-resident memory CD8+ T (TRM) cells that develop in the epithelia at portals of pathogen entry are important for improved protection against re-infection. CD8+ TRM cells within the skin and the small intestine are long-lived and maintained independently of circulating memory CD8+ T cells. In contrast to CD8+ TRM cells at these sites, CD8+ TRM cells that arise after influenza virus infection within the lungs display high turnover and require constant recruitment from the circulating memory pool for long-term persistence. The distinct characteristics of CD8+ TRM cell maintenance within the lungs may suggest a unique program of transcriptional regulation of influenza-specific CD8+ TRM cells. We have previously demonstrated that the transcription factors Hobit and Blimp-1 are essential for the formation of CD8+ TRM cells across several tissues, including skin, liver, kidneys, and the small intestine. Here, we addressed the roles of Hobit and Blimp-1 in CD8+ TRM cell differentiation in the lungs after influenza infection using mice deficient for these transcription factors. Hobit was not required for the formation of influenza-specific CD8+ TRM cells in the lungs. In contrast, Blimp-1 was essential for the differentiation of lung CD8+ TRM cells and inhibited the differentiation of central memory CD8+ T (TCM) cells. We conclude that Blimp-1 rather than Hobit mediates the formation of CD8+ TRM cells in the lungs, potentially through control of the lineage choice between TCM and TRM cells during the differentiation of influenza-specific CD8+ T cells.

In a Mars exploration scenario, knowing if and how highly resistant Bacillus subtilis spores would survive on the Martian surface is crucial to design planetary protection measures and avoid false positives in life-detection experiments. Therefore, in this study a systematic screening was performed to determine whether B. subtilis spores could survive an average day on Mars. For that, spores from two comprehensive sets of isogenic B. subtilis mutant strains, defective in DNA protection or repair genes, were exposed to 24 h of simulated Martian atmospheric environment with or without 8 h of Martian UV radiation [M(+)UV and M(-)UV, respectively]. When exposed to M(+)UV, spore survival was dependent on: (1) core dehydration maintenance, (2) protection of DNA by α/β-type small acid soluble proteins (SASP), and (3) removal and repair of the major UV photoproduct (SP) in spore DNA. In turn, when exposed to M(-)UV, spore survival was mainly dependent on protection by the multilayered spore coat, and DNA double-strand breaks represent the main lesion accumulated. Bacillus subtilis spores were able to survive for at least a limited time in a simulated Martian environment, both with or without solar UV radiation. Moreover, M(-)UV-treated spores exhibited survival rates significantly higher than the M(+)UV-treated spores. This suggests that on a real Martian surface, radiation shielding of spores (e.g., by dust, rocks, or spacecraft surface irregularities) might significantly extend survival rates. Mutagenesis were strongly dependent on the functionality of all structural components with small acid-soluble spore proteins, coat layers and dipicolinic acid as key protectants and efficiency DNA damage removal by AP endonucleases (ExoA and Nfo), non-homologous end joining (NHEJ), mismatch repair (MMR) and error-prone translesion synthesis (TLS). Thus, future efforts should focus on: (1) determining the DNA damage in wild-type spores exposed to M(+/-)UV and (2) assessing spore survival and viability with shielding of spores via Mars regolith and other relevant materials.

Dps proteins (DNA-binding proteins from starved cells) have been found to detoxify H2O2. At their catalytic centers, the ferroxidase center (FOC), Dps proteins utilize Fe2+ to reduce H2O2 and therefore play an essential role in the protection against oxidative stress and maintaining iron homeostasis. Whereas most bacteria accommodate one or two Dps, there are five different Dps proteins in Nostoc punctiforme, a phototrophic and filamentous cyanobacterium. This uncommonly high number of Dps proteins implies a sophisticated machinery for maintaining complex iron homeostasis and for protection against oxidative stress. Functional analyses and structural information on cyanobacterial Dps proteins are rare, but essential for understanding the function of each of the NpDps proteins. In this study, we present the crystal structure of NpDps4 in its metal-free, iron- and zinc-bound forms. The FOC coordinates either two iron atoms or one zinc atom. Spectroscopic analyses revealed that NpDps4 could oxidize Fe2+ utilizing O2, but no evidence for its use of the oxidant H2O2 could be found. We identified Zn2+ to be an effective inhibitor of the O2-mediated Fe2+ oxidation in NpDps4. NpDps4 exhibits a FOC that is very different from canonical Dps, but structurally similar to the atypical one from DpsA of Thermosynechococcus elongatus. Sequence comparisons among Dps protein homologs to NpDps4 within the cyanobacterial phylum led us to classify a novel FOC class: the His-type FOC. The features of this special FOC have not been identified in Dps proteins from other bacterial phyla and it might be unique to cyanobacterial Dps proteins.

BackgroundIn many low- and middle-income countries, data on the prevalence of surgical diseases have been derived primarily from hospital-based studies, which may lead to an underestimation of disease burden within the community. Community-based prevalence studies may provide better estimates of surgical need to enable proper resource allocation and prioritization of needs. This study aims to assess the prevalence of common surgical conditions among children in a diverse rural and urban population in Nigeria.MethodsDescriptive cross-sectional, community-based study to determine the prevalence of congenital and acquired surgical conditions among children in a diverse rural-urban area of Nigeria was conducted. Households, defined as one or more persons 'who eat from the same pot' or slept under the same roof the night before the interview, were randomized for inclusion in the study. Data was collected using an adapted and modified version of the interviewer-administered questionnaire-Surgeons OverSeas Assessment of Surgical Need (SOSAS) survey tool and analysed using the REDCap web-based analytic application.Main resultsEight-hundred-and-fifty-six households were surveyed, comprising 1,883 children. Eighty-one conditions were identified, the most common being umbilical hernias (20), inguinal hernias (13), and wound injuries to the extremities (9). The prevalence per 10,000 children was 85 for umbilical hernias (95% CI: 47, 123), and 61 for inguinal hernias (95% CI: 34, 88). The prevalence of hydroceles and undescended testes was comparable at 22 and 26 per 10,000 children, respectively. Children with surgical conditions had similar sociodemographic characteristics to healthy children in the study population.ConclusionThe most common congenital surgical conditions in our setting were umbilical hernias, while injuries were the most common acquired conditions. From our study, it is estimated that there will be about 2.9 million children with surgically correctable conditions in the nation. This suggests an acute need for training more paediatric surgeons.

IntroductionBrown adipose tissue (BAT) is considered as a potential target for combating obesity in humans where active BAT metabolizes glucose and fatty acids as fuel resulting in heat production. Prospective studies in humans have been set up to further study the presence and metabolic activity of BAT mostly using Positron Emission Tomography (PET) imaging in cold-stimulated conditions with the radiolabeled glucose derivative [18F]FDG. However, radiotracers beyond [18F]FDG have been proposed to investigate BAT activity, targeting various aspects of BAT metabolism. It remains questionable which tracer is best suited to detect metabolic BAT activity and to what extent those results correlate with ex vivo metabolic BAT activity.MethodsPET and Single Photon Emission Computed Tomography (SPECT) imaging, targeting different aspects of BAT activation such as glucose metabolism, fatty acid metabolism, noradrenergic stimulation, blood perfusion and amino acid transport system, was performed immediately after injection of the tracer in rats under different temperatures: room temperature, acute cold (4 ⁰C for 4 h) or acclimated to cold (4 ⁰C for 6 h per day during 28 days). Furthermore, Magnetic Resonance Spectroscopy (MRS)-derived BAT temperature was measured in control and cold-acclimated rats.ResultsAt room temperature, only [18F]FDG visualized BAT. Glucose metabolism, fatty acid metabolism, noradrenergic stimulation and blood perfusion showed a clear tracer-dependent twofold increase in BAT uptake upon cold exposure. Only the tracer for the amino acid transport system did not show BAT specific uptake under any of the experimental conditions. MRS demonstrated that cold-acclimated animals had BAT with a stronger heat-production compared to control animals.ConclusionBAT activity following cold exposure in rats was visualized by several tracers, while only [18F]FDG was also able to show BAT activity under non-stimulated conditions (room temperature). The variances in uptake of the different tracers should be taken into account when developing future clinical applications in humans.

Hypothyroidism is common, with an extreme manifestation of myxedema coma if untreated. Hematologic consequences of myxedema coma include mild leukopenia and anemia, rarely pancytopenia. We present a patient with typical symptoms of myxedema coma, but found to be pancytopenic, with sustained response to levothyroxine and blood transfusion for anemia.