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Background and Objectives: As new models of care aiming to reduce hospitalizations from nursing homes emerge, their implementers must consider residents' and relatives' needs and experiences with acute changes in the residents' health situations. As part of the larger INTERCARE implementation study, we explored these persons' experiences of acute situations in Swiss nursing homes., Research Design and Methods: 3 focus groups were conducted with residents and their relatives and analyzed via reflexive thematic analysis., Results: The first theme, the orchestra plays its standards, describes experiences of structured everyday care in nursing homes, which functions well despite limited professional and competency resources. The second theme, the orchestra reaches its limits, illustrates accounts of acute situations in which resources were insufficient to meet residents' needs. Interestingly, participants' perceptions of acute situations went well beyond our own professional view, that is, changes in health situations, and included situations best summarized as "changes that might have negative consequences for residents if not handled adequately by care workers." Within the third theme, the audience compensates for the orchestra's limitations, participants' strategies to cope with resource limitations in acute situations are summarized., Discussion and Implications: Our findings suggest differences between care providers' and participants' perspectives regarding acute situations and care priority setting. Alongside efforts to promote staff awareness of and responsiveness to acute situations, care staff must commit to learning and meeting individual residents' and relatives' needs. Implications for the development and implementation of a new nurse-led model of care are discussed., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: The advent of mobile applications for health and medicine will revolutionize travel medicine. Despite their many benefits, such as access to real-time data, mobile apps for travel medicine are accompanied by many ethical issues, including questions about security and privacy., Methods: A systematic literature review as conducted following PRISMA guidelines. Database screening yielded 1795 results and seven papers satisfied the criteria for inclusion. Through a mix of inductive and deductive data extraction, this systematic review examined both the benefits and challenges, as well as ethical considerations, of mobile apps for travel medicine., Results: Ethical considerations were discussed with varying depth across the included articles, with privacy and data protection mentioned most frequently, highlighting concerns over sensitive information and a lack of guidelines in the digital sphere. Additionally, technical concerns about data quality and bias were predominant issues for researchers and developers alike. Some ethical issues were not discussed at all, including equity, and user involvement., Conclusion: This paper highlights the scarcity of discussion around ethical issues. Both researchers and developers need to better integrate ethical reflection at each step of the development and use of health apps. More effective oversight mechanisms and clearer ethical guidance are needed to guide the stakeholders in this endeavour., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Purpose: A single-isocenter stereotactic body radiotherapy (SBRT) approach for multiple lung metastases has the potential to lower cumulative patient dose and reduce overall treatment time. However, the magnitude of inter-lesion position variation is currently unknown and not incorporated in margin calculations. The aim of this study was to quantify inter-lesion position variation and calculate safety margins for single-isocenter lung SBRT., Materials and Methods: A total of 83 pairs of pulmonary metastases from 42 NSCLC patients were used to calculate relative inter-lesion position variation by lesion-based registration of planning CT and verification CBCT. Furthermore, β-value assessment of van Herk's margin formula was performed by evaluating the distance between planned and blurred dose profiles of simulated spherical lesions, to evaluate its validity for heterogeneously planned dose distributions. Population-based ITV to PTV margins were calculated using the entire dataset and using subgroups with significant differences in relative inter-lesion position variation., Results: The mean ± SD inter-lesion position variation was 1.2 ± 1.1 mm as 3D-vector. Inter-lesion position variation was significantly increased if ≥1 lesion was not attached to the pleura or lesions were distant. The simulation showed that the combined SD of the random errors contributed to the margin only in the SI direction with 0.25∙σ tot for a 65% dose prescription. When incorporating inter-lesion position variation, the safety margins increased from 5.6, 5.8, 5.2 mm (AP, SI, LR) to 6.0, 6.6, 5.5 mm for the entire cohort., Conclusion: Relative inter-lesion position variation is influenced by inter-target distance and location and can be compensated with additional safety margins of <1 mm using single-isocenter SBRT., Competing Interests: Conflict of interest statement Dr. Hoogeman reports grants from Elekta, grants from Accuracy, grants from Varian, other from Accuracy, outside the submitted work. Dr. Tanadini-Lang reports that her husband works at Varian Medical Systems. Dr. van Timmeren, dr. Ehrbar, dr. Mayinger, dr. Andratschke and dr. Guckenberger report no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Antisense oligonucleotides (ASOs) are chemically modified nucleic acids with therapeutic potential, some of which have been approved for marketing. We performed a study in rats to investigate mechanisms of toxicity after administration of 3 tool locked nucleic acid (LNA)-containing ASOs with differing established safety profiles. Four male rats per group were dosed once, 3, or 6 times subcutaneously, with 7 days between dosing, and sacrificed 3 days after the last dose. These ASOs were either unconjugated (naked) or conjugated with N-acetylgalactosamine for hepatocyte-targeted delivery. The main readouts were in-life monitoring, clinical and anatomic pathology, exposure assessment and metabolite identification in liver and kidney by liquid chromatography coupled to tandem mass spectrometry, ASO detection in liver and kidney by immunohistochemistry, in situ hybridization, immune electron microscopy, and matrix-assisted laser desorption/ionization mass spectrometry imaging. The highly toxic compounds showed the greatest amount of metabolites and a low degree of tissue accumulation. This study reveals different patterns of cell death associated with toxicity in liver (apoptosis and necrosis) and kidney (necrosis only) and provides new ultrastructural insights on the tissue accumulation of ASOs. We observed that the immunostimulatory properties of ASOs can be either primary from sequence-dependent properties or secondary to cell necrosis.

Background . The prediction of functional outcomes after spinal cord injury (SCI) is essential to plan the rehabilitation phase and the social reintegration. Recently, 2 models to predict independent and reliable bowel management 1 year after traumatic SCI have been derived and validated in 2 cohorts of patients included in the European Multicenter Study about Spinal Cord Injury (EMSCI). Objective . We aimed to validate 2 prediction models for bowel outcome after traumatic SCI in a patient sample external to EMSCI. Methods . The simplified model (based on a single predictor, the International Standards for Neurological Classification of Spinal Cord Injury [ISNCSCI] total motor score) and the full model (based on 2 predictors, the ISNCSCI total motor score and item 3a of the Spinal Cord Independence Measure) were applied to the retrospectively collected data of 111 patients with traumatic SCI. Results . The simplified and the full models showed excellent discrimination with an area under the receiver operating characteristic curve of .939 (95% confidence interval (CI) .87-1.00) and .922 (95% CI 0.85-.99), respectively. Both models displayed similar results for sensitivity and negative predictive values; however, the simplified model showed higher values for specificity, positive predictive values, and accuracy. The calibration analysis showed a partial overlap between predicted probabilities and observed proportion, with better and acceptable calibration for the simplified model. Conclusions . Using an independent sample, our study demonstrates the validity of a simple model to predict independent and reliable bowel management 1 year after traumatic SCI.

Ezrin-Radixin-Moesin (ERM) proteins play an essential role in the cytoplasm by cross-linking actin filaments with plasma membrane proteins. Research has identified the nuclear localization of ERMs, as well as the involvement of a single Drosophila ERM protein, Moesin, in nuclear mRNA exports. However, the question of how important the nuclear activity of ERM proteins are for the life of an organism has so far not been explored. Here, we present the first attempt to reveal the in vivo relevance of nuclear localization of Moesin in Drosophila. With the help of a nuclear export signal, we decreased the amount of Moesin in the nuclei of the animals. Furthermore, we observed various developmental defects, demonstrating the importance of ERM function in the nucleus for the first time. Transcriptome analysis of the mutant flies revealed that the lack of nuclear Moesin function leads to expression changes in nearly 700 genes, among them heat-shock genes. This result together with additional findings revealed that in Drosophila the expression of protein chaperones requires the nuclear functions of Moesin. DATABASE: GEO accession number: GSE155778., (© 2021 The Authors. The FEBS Journal published by John Wiley & Ltd on behalf of Federation of European Biochemical Societies.)

Fueled by the global surge in aging, atherosclerotic cardiovascular disease reached pandemic dimensions putting affected individuals at enhanced risk of myocardial infarction, stroke, and premature death. Atherosclerosis is a systemic disease driven by a wide spectrum of factors, including cholesterol, pressure, and disturbed flow. Although all arterial beds encounter a similar atherogenic milieu, the development of atheromatous lesions occurs discontinuously across the vascular system. Indeed, the internal mammary artery possesses unique biological properties that confer protection to intimal growth and atherosclerotic plaque formation, thus making it a conduit of choice for coronary artery bypass grafting. Its endothelium abundantly expresses nitric oxide synthase and shows accentuated nitric oxide release, while its vascular smooth muscle cells exhibit reduced tissue factor expression, high tPA (tissue-type plasminogen activator) production and blunted migration and proliferation, which may collectively mitigate intimal thickening and ultimately the evolution of atheromatous plaques. We aim here to provide insights into the anatomy, physiology, cellular, and molecular aspects of the internal mammary artery thereby elucidating its remarkable resistance to atherogenesis. We propose a change in perspective from risk to resilience to decipher mechanisms of atheroresistance and eventually identification of novel therapeutic targets presently not addressed by currently available remedies.

Exposure to trauma is considered a risk factor for the development of addictive disorders. Currently, there is a knowledge gap concerning specific links between types and levels of exposure to traumatic events and addiction.In this study we explored the associations between interpersonal trauma and risk of addictive behaviors, stratified by type of trauma (physical, weapon, sexual assault, and combat) and level of exposure (direct/indirect), focusing on a wide range of substances and behaviors. Data from an online representative sample of 4025 respondents were collected, including the Life Events Checklist (LEC-5), substance use disorders and behavioral addictions metrics, and sociodemographic data. Substantial differences were found between specific types of trauma and risk of addiction. Among those exposed to sexual assault, the risk of alcohol use disorder was found to 15.4%, 95%CI[14.4-16.4%], compared to 12.1%,95%CI[11.3-12.8] among those exposed to combat-related trauma. Both direct and indirect exposure to trauma were found to be significantly related with risk of addiction. While direct exposure was most highly associated with addictions across several types of trauma, in the case of combat-related trauma, indirect exposure was more highly associated with alcohol and pornography addiction (14.5%,95%CI[13.2-15.8%] and 10.0%, 95%CI[6.3-15.0%], respectively) compared to direct exposure (10.7%,95%CI[9.9-11.6%] and 7.4%, 95%CI[4.7-11.6%], respectively). Our findings emphasize the strong association between all types of trauma and the risk of several specific substance and behavioral addictions. Specifically, the role of indirect exposure to trauma is highlighted., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Viable eggs of the canine intestinal tapeworm Echinococcus granulosus sensu lato (s.l.) infect various intermediate hosts causing cystic echinococcosis (CE). Furthermore, CE represents a serious zoonosis causing a significant global burden of disease. CE is highly endemic in South America, including Argentina, Brazil, Chile, Uruguay, and Peru. For Bolivia, no official data concerning the incidence in humans or the number of livestock and dogs infected are available. However, it is well known that CE occurs in Bolivia. We aim here to fill the gap in the current knowledge of the epidemiological situation of CE in Bolivia, providing a historical overview of documents published within the country, which have never been comprehensively reviewed. The very first documentation of E. granulosus infection in animals dates in 1910, while the first human case was reported in 1913. In total, 876 human CE cases have been reported in the scientific literature, with an apparent increase since the 1970s. In the absence of other epidemiological studies, the highest prevalence in human comes from Tupiza, Potosí Department, where 4.1% (51/1,268) of the population showed signs of CE at mass ultrasound screening in 2011. In the same report, 24% of dog faecal samples were positive for coproantigens of E. granulosus s.l. in ELISA. The highest prevalence in intermediate hosts reported at abattoir reached 37.5% in cattle from Potosí, followed by 26.9% in llamas from Oruro, 2.4% in pigs and 1.4% in sheep from La Paz. Finally, Echinococcus granulosus sensu stricto (s.s.), Echinococcus ortleppi (G5), and Echinococcus intermedius (G7) have been identified in Bolivia. Data reviewed here confirm that E. granulosus s.l. is circulating in Bolivia and that a proper prospective nationwide epidemiological study of CE is urgently needed to define transmission patterns as a basis for the planning and implementation of future control measurements., Competing Interests: The authors have declared that no competing interests exist.

Takotsubo Syndrome (TTS) is characterized by a transient left ventricular dysfunction recovering spontaneously within days or weeks. Although the pathophysiology of TTS remains obscure, there is growing evidence suggesting TTS to be associated with increased production of reactive oxygen species (ROS), which may be involved in causing transient coronary and peripheral endothelial dysfunction leading to a transient impairment of myocardial contraction due to stunning (apical ballooning). Endothelial dysfunction is mainly caused by decreased vascular and myocardial nitric oxide bioavailability in response to increased ROS production. Accordingly, studies in humans and animal models demonstrated increased myocardial dihydroethidium staining of the myocardium in endomyocardial biopsy specimens, increased levels of hydrogen peroxide and malondialdehyde as well as reduced glutathione levels compatible with increased oxidative stress. As significant superoxide sources the mitochondria and the NADPH oxidase isoform NOX-4 and the NOX-2 regulating cytosolic subunit p67phox have been identified. Treatment with antioxidants such as sodium hydrosulfide reduced superoxide production in mitochondria and reduced expression of NOX-4 and p67phox, respectively. The presence of superoxide and nitric oxide also provides the basis for the concept of nitro-oxidative as well as nitrosative stress in TTS., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The evolution of the nucleus is an evolutionary milestone. By enabling genome compartmentalization, it contributes to the fine-tuning of genome functions. The genome is partitioned into functional domains differing in spatial positioning and topological folding at different scales. The rise of '3D Genomics' embracing experimental, theoretical, and modeling approaches allowed the proposal of a multiscale model of the eukaryotic genome, capturing its organizing principles and functionalities. In these efforts, resolving causality remains an important objective. Are positioning and folding the cause or consequence of functional states? This minireview presents emerging answers to this question, borrowing examples from recent studies of the three-dimensional genome in both plants and animals., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: To measure tooth movement 1 week post-treatment and assess potential correlation with changes invoked during treatment., Subjects and Methods: Thirty-eight patients were recruited (19 males, 19 females). Polyvinyl siloxane impressions were taken after bracket debonding (T1) and 1 week later (T2) and digitally scanned. During this period no retention was used. The digital casts were superimposed on structures of the hard palate. Translation and rotation of the first molars, canines, and central incisors were recorded. Additionally, movement of these teeth was assessed from the beginning (T0) until the end of treatment (T1). The correlation between the post-treatment relapse (T1-T2) and tooth movement during treatment (T0-T1) was investigated via the Spearman correlation coefficient., Results: Relapse was detected and reflected changes in tooth position during treatment. For the first molars (right, left) the correlation between treatment and post-treatment tooth movement was evident in the transverse direction (r = -0.38, P = 0.020; r = -0.32, P = 0.052), tipping (r = -0.40, P = 0.015; r = -0.34, P = 0.034) and the antero-posterior direction (r = -0.31, P = 0.061; r = -0.36, P = 0.027); for the canines (right and left), as rotation around their long axis (r = -0.55, P = 0.003; r = -0.58, P = 0.002); for central incisors (right and left) in the antero-posterior direction (r = -0.55, P = 0.000; r = -0.48, P = 0.03), transverse direction (r = -0.43, P = 0.07; r = -0.32, P = 0.047), and rotation around their long axis (r = -0.53, P = 0.001; r = -0.28, P = 0.089)., Conclusions: Post-treatment changes in tooth position were mostly related to tooth movement during treatment. The reported correlations may help clinicians predict short-term relapse, evaluate long-term retention need, and design individualized retention schemes., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background Recurrence of mitral regurgitation (MR) after surgical mitral valve repair (SMVR) varies and may require reoperation. Redo mitral valve surgery can be technically challenging and is associated with increased risk of mortality and morbidity. We aimed to assess the feasibility and safety of MitraClip as a treatment strategy after failed SMVR and identify procedure modifications to overcome technical challenges. Methods and Results This international multicenter observational retrospective study collected information for all patients from 16 high-volume hospitals who were treated with MitraClip after failed SMVR from October 29, 2009, until August 1, 2017. Data were anonymously collected. Technical and device success were recorded per modified Mitral Valve Academic Research Consortium criteria. Overall, 104 consecutive patients were included. Median Society of Thoracic Surgeons score was 4.5% and median age was 73 years. At baseline, the majority of patients (82%) were in New York Heart Association class ≥III and MR was moderate or higher in 86% of patients. The cause of MR pre-SMVR was degenerative in 50%, functional in 35%, mixed in 8%, and missing/unknown in 8% of patients. The median time between SMVR and MitraClip was 5.3 (1.9-9.7) years. Technical and device success were 90% and 89%, respectively. Additional/modified imaging was applied in 21% of cases. An MR reduction of ≥1 grade was achieved in 94% of patients and residual MR was moderate or less in 90% of patients. In-hospital all-cause mortality was 2%, and 86% of patients were in New York Heart Association class ≤II. Conclusions MitraClip is a safe and less invasive treatment option for patients with recurrent MR after failed SMVR. Additional/modified imaging may help overcome technical challenges during leaflet grasping.

In humans, the combination of all sex-specific genetic, epigenetic, and hormonal influences of biologic sex produces different in vivo environments for male and female cells. We dissect how these influences of sex modify the pharmacokinetics and pharmacodynamics of multiple drugs and provide examples for common drugs acting on specific organ systems. We also discuss how gender of physicians and patients may influence the therapeutic response to drugs. We aim to highlight sex as a genetic modifier of the pharmacological response to drugs, which should be considered as a necessary step toward precision medicine that will benefit men and women. SIGNIFICANCE STATEMENT: This study discusses the influences of biologic sex on the pharmacokinetics and pharmacodynamics of drugs and provides examples for common drugs acting on specific organ systems. This study also discusses how gender of physicians and patients influence the therapeutic response to drugs., Competing Interests: Financial disclosure statement No authors have an actual or perceived conflict of interest with the contents of this article., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

The folate and methionine cycles, constituting one-carbon metabolism, are critical pathways for cell survival. Intersecting these two cycles, 5,10-methylenetetrahydrofolate reductase (MTHFR) directs one-carbon units from the folate to methionine cycle, to be exclusively used for methionine and S-adenosylmethionine (AdoMet) synthesis. MTHFR deficiency and upregulation result in diverse disease states, rendering it an attractive drug target. The activity of MTHFR is inhibited by the binding of AdoMet to an allosteric regulatory domain distal to the enzyme's active site, which we have previously identified to constitute a novel fold with a druggable pocket. Here, we screened 162 AdoMet mimetics using differential scanning fluorimetry, and identified 4 compounds that stabilized this regulatory domain. Three compounds were sinefungin analogues, closely related to AdoMet and S-adenosylhomocysteine (AdoHcy). The strongest thermal stabilisation was provided by (S)-SKI-72, a potent inhibitor originally developed for protein arginine methyltransferase 4 (PRMT4). Using surface plasmon resonance, we confirmed that (S)-SKI-72 binds MTHFR via its allosteric domain with nanomolar affinity. Assay of MTHFR activity in the presence of (S)-SKI-72 demonstrates inhibition of purified enzyme with sub-micromolar potency and endogenous MTHFR from HEK293 cell lysate in the low micromolar range, both of which are lower than AdoMet. Nevertheless, unlike AdoMet, (S)-SKI-72 is unable to completely abolish MTHFR activity, even at very high concentrations. Combining binding assays, kinetic characterization and compound docking, this work indicates the regulatory domain of MTHFR can be targeted by small molecules and presents (S)-SKI-72 as an excellent candidate for development of MTHFR inhibitors., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Competing Interests: The authors have declared that no competing interests exist.

Background: Silexan is a lavender essential oil with established anxiolytic and calming efficacy. Here we asked whether there is a potential for abuse in human patients., Methods: We carried out a phase I abuse liability single-center, double-blind, 5-way crossover study in healthy users of recreational central nervous system depressants. They received single oral doses of 80 mg (therapeutic dose) and 640 mg Silexan, 2 mg and 4 mg lorazepam (active control) and placebo in randomized order, with 4- to 14-day washout periods between treatments. Pharmacodynamic measures included validated visual analogue scales assessing positive, negative, and sedative drug effects and balance of effects; a short form of the Addiction Research Center Inventory; and a drug similarity assessment. The primary outcome measure was the individual maximum value on the drug liking visual analogue scale during 24 hours post-dose., Results: Forty participants were randomized and 34 were evaluable for pharmacodynamic outcomes. In intraindividual head-to-head comparisons of the drug liking visual analogue scale maximum value, both doses of Silexan were rated similar to placebo whereas differences were observed between Silexan and lorazepam and between placebo and lorazepam (P < .001). These data were supported by all secondary measures of positive drug effects and of balance of effects. Differences between placebo and both doses of Silexan were always negligible in magnitude. Moreover, Silexan showed no sedative effects and was not perceived to be similar to commonly used drugs that participants had used in the past., Conclusions: Silexan did not exhibit any abuse potential in a standard abuse potential detection screen study and is unlikely to be recreationally abused., (© The Author(s) 2020. Published by Oxford University Press on behalf of CINP.)

Prediabetes is often observed in patients with Metabolic Syndrome (MetS) and might be associated with metabolic and inflammatory alterations. Here, we investigated whether the inflammatory molecule osteopontin (OPN) might have a prognostic impact in a cohort of MetS patients (n = 85) with baseline normal glycaemia or impaired fasting glucose (IFG) over one year of recommended pharmacological treatments and Mediterranean diet. Patients were then followed up for 12 months with intermediate evaluation after 6 months. At all time points, anthropometric and clinical data were recorded, alongside with haematological and biochemical profiles, including serum concentrations of OPN. As expected, Mediterranean diet improves glycaemic profile in patients with IFG. Baseline serum OPN failed to be associated with baseline anthropometric or biochemical variables. At baseline, higher levels of OPN were shown in patients with IFG as compared to normal glycaemia. Two distinct subgroups of patients in whom OPN decreased or remained stable/increased at follow-up were identified. When higher serum OPN levels were observed at baseline, greater reduction was observed at 1-year follow-up. Reduction in circulating OPN levels was associated with metabolic improvement in terms of blood pressure, LDL-c, HDL-c, and glycaemia. At both univariate and adjusted logistic regression analyses, serum OPN emerged as an independent predictor of glycaemic profile improvement at 1-year follow-up (adjOR 1.05 [1.00-1.10]; P = .041). In conclusion, pharmacological and dietetic interventions improved glycaemic profile in patients with MetS. In particular, glycaemic improvement was demonstrated in patients who also reduce circulating OPN levels. Higher OPN levels at baseline predict normalization of glycaemic profile., (© 2020 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Epstein Barr virus (EBV) is the most common human tumor virus, persistently infecting more than 95% of the human adult population and readily transforming human B cell in culture. Fortunately, only a small minority of EBV carriers develops virus associated malignancies. The majority controls persistent EBV infection with cytotoxic lymphocytes, mainly NK, γδ and CD8 + T cells and the characteristics of the required immune responses get more and more defined by primary immunodeficiencies that affect molecules of these cytotoxic lymphocytes and their investigation in mice with reconstituted human immune system components (humanized mice) that are susceptible to EBV infection and associated lymphomagenesis. The gained information should be able to guide us to develop immunotherapies against EBV and tumors in general., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Driven by the current unsatisfactory outcomes for patients with locally advanced pancreatic cancer (LAPC), a biologically intensified clinical protocol was developed to explore the feasibility and efficacy of FOLFORINOX chemotherapy followed by deep hyperthermia concomitant with chemoradiation and subsequent FOLFORINOX chemotherapy in patients with LAPC., Methods: Nine patients with LAPC were treated according to the HEATPAC Phase II trial protocol which consists of 4 cycles of FOLFORINOX chemotherapy followed by gemcitabine-based chemoradiation to 56 Gy combined with weekly deep hyperthermia and then a further 8 cycles of FOLFORINOX chemotherapy., Results: One grade three related toxicity was reported and two tumours became resectable. The median overall survival was 24 months and 1 year overall survival was 100%., Conclusions: Intensification of chemoradiation with deep hyperthermia was feasible in nine consecutive patients with LAPC., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

The development of tailored materials for specific applications is an active field of research in chemistry, material science and drug discovery. The number of possible molecules obtainable from a set of atomic species grow exponentially with the size of the system, limiting the efficiency of classical sampling algorithms. On the other hand, quantum computers can provide an efficient solution to the sampling of the chemical compound space for the optimization of a given molecular property. In this work, we propose a quantum algorithm for addressing the material design problem with a favourable scaling. The core of this approach is the representation of the space of candidate structures as a linear superposition of all possible atomic compositions. The corresponding 'alchemical' Hamiltonian drives the optimization in both the atomic and electronic spaces leading to the selection of the best fitting molecule, which optimizes a given property of the system, e.g. , the interaction with an external potential as in drug design. The quantum advantage resides in the efficient calculation of the electronic structure properties together with the sampling of the exponentially large chemical compound space. We demonstrate both in simulations and with IBM Quantum hardware the efficiency of our scheme and highlight the results in a few test cases. This preliminary study can serve as a basis for the development of further material design quantum algorithms for near-term quantum computers., Competing Interests: The authors declare no competing interests., (This journal is © The Royal Society of Chemistry.)

The glycoprotein IIb/IIIa inhibitor eptifibatide, administered as bolus followed by infusion, is an adjunctive antithrombotic treatment during primary percutaneous coronary intervention (PCI) in selected patients with ST-segment elevation myocardial infarction (STEMI). Whether both bolus and infusion are necessary to improve outcomes is unknown. We hypothesized that primary PCI with eptifibatide bolus only is non-inferior to the conventional treatment (bolus and infusion) with regard to infarct size, while reducing bleeding complications. We analyzed 720 consecutive STEMI patients receiving eptifibatide bolus only or conventional treatment in an observational case-control study utilizing propensity score matching of clinical and intervention-specific confounders. Infarct size was estimated based on myocardial bound creatine kinase, creatine kinase (CK), and CK area under the curve values, with a prespecified non-inferiority margin of 20%. Major bleeding was defined as type 2, 3, or 5 on the Bleeding Academic Research Consortium classification. Eptifibatide bolus only was administered to 147 patients (20%), which were matched 1:1 to patients receiving conventional treatment. Based on peak myocardial bound creatine kinase, CK and CK area under the curve values, infarct size was -8.4% (95% CI [-31.2%, 14.4%]), -11.6% (95% CI [-33.5%, 10.3%]), and -13.9% (95% CI [-34.1%, 6.2%]) after eptifibatide bolus, respectively, reaching prespecified noninferiority compared with conventional treatment. Bolus treatment significantly reduced major bleeding complications (OR 0.48, 95% CI [0.30, 0.79]). In conclusion, eptifibatide given as abbreviated bolus only to selected STEMI patients who underwent primary PCI was noninferior regarding infarct size and resulted in less bleeding complications compared with conventional bolus and infusion treatment., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The worldwide prevalence of dementia is increasing and represents a major public health concern. In the last decades, air travel services have undergone an impressive expansion and one of ten passengers is aged 65 years and older. While air travel can be stressful at all ages and health conditions, older individuals with cognitive impairment carry a greater risk for air-travel-related complications. Consequently, demands to general practitioners for assessing their older patient's fitness to fly are increasing., Methods: We conducted a search of the literature in PubMed on the impact of in-flight environmental changes on passengers with cognitive impairment and possible resulting complications. This set the base for a discussion on pharmacological and non-pharmacological interventions aimed at preventing in-flight complications in this vulnerable population., Results: While our research strategy identified a total of 11 articles related to older age and air travel, only three focused on passengers with cognitive impairment. Our literature review showed that the airplane environment may lead to a large spectrum of symptoms in passengers of all age groups. However, passengers with cognitive impairment due to neurodegenerative diseases are at increased risk for experiencing the most extreme symptoms such as acute confusional state. Non-pharmacological and pharmacological interventions at different stages of the travel process (before, during and after) can help prevent complications in this vulnerable population., Conclusion: The decision to let a patient with cognitive impairment fly requires a solid understanding of the in-flight environmental changes and their impact on older patients with cognitive impairment. Moreover, a sound weighing of the risks and benefits while considering different aspects of the patient's history is demanded. In this regard, the role of the treating physicians and caregivers is essential along with the support of the medical department of the airline., (© International Society of Travel Medicine 2020. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The Community Action Programme for Education and Training for Technology (COMETT) played a key role in paving the way for increased cooperation between the member states of the European Community (EC) in the field of education and in the promotion of intra-Europe mobility. In this article, COMETT is considered as a non-traditional education and training programme for solving economic challenges in the context of technological change that was focused on the training of a highly skilled workforce. The process of setting the agenda for COMETT is studied through an analysis of official EC policy documents and archival material from the EU's historical archives in Florence. Our analysis suggests that the challenge posed by new information technologies acted as a catalyst for a new approach to education governance that was based on closer cooperation between European universities and industry. Promoting intra-Europe mobility among highly skilled workers and students was a key part of the programme, which defined an economic and social strategy for Europe in response to technological change. Educational and social goals were secondary in the design and implementation of the COMETT programme, which, first and foremost, was motivated by the EC agenda to boost the competitiveness of European industry., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Background The role of microRNAs dysregulation in tobacco cigarette smoking-induced vascular damage still needs to be clarified. We assessed the acute effects of tobacco cigarette smoking on endothelial cell-related circulating microRNAs in healthy subjects. In addition, we investigated the potential role of microRNAs in smoking-dependent endothelial cell damage. Methods and Results A panel of endothelial-related microRNAs was quantified in healthy subjects before and after smoking 1 tobacco cigarette. Serum levels of miR-155 were found to be significantly increased shortly after smoking. We also observed a progressive and significant miR-155 accumulation in culture media of human endothelial cells after 30 minutes and up to 4 hours of cigarette smoke condensate treatment in vitro without evidence of cell death, indicating that miR-155 can be released by endothelial cells in response to smoking stress. Cigarette smoke condensate appeared to enhance oxidative stress and impair cell survival, angiogenesis, and NO metabolism in human endothelial cells. Notably, these effects were abrogated by miR-155 inhibition. We also observed that miR-155 inhibition rescued the deleterious effects of cigarette smoke condensate on endothelial-mediated vascular relaxation and oxidative stress in isolated mouse mesenteric arteries. Finally, we found that exogenous miR-155 overexpression mimics the effects of smoking stress by inducing the upregulation of inflammatory markers, impairing angiogenesis and reducing cell survival. These deleterious effects were associated with downregulation of vascular endothelial growth factor and endothelial NO synthetase. Conclusions Our results suggest that miR-155 dysregulation may contribute to the deleterious vascular effects of tobacco smoking.

Objectives: This paper presents an overview of the policy responses in Germany, Austria and Switzerland (the DACH region) during the early stages of the 2020 Covid-19 pandemic (Feb.-June 2020), which provides the context for a comparative policy analysis. This analysis provides insight into the possible implications of the policy actions taken in the region., Methods: An in-depth review and analysis of available data from the DACH countries was conducted. Data was collected from official government sources whenever possible, and supplemented by information from international databases and local reports. The data was then analyzed to identify common patterns as well as significant divergences across the DACH region, especially in the area of health policy and technology use., Results: The DACH countries faced similar epidemiological situations during the Covid-19 pandemic, and were largely successful at preventing many of the negative impacts seen across the rest of Europe. Although many differences in health systems and governance structures existed, the policy responses in all three countries managed to address some of the most important factors in containing an infectious disease outbreak of this magnitude., Conclusions: The actions taken by all three DACH countries appear to have been largely successful in reducing the health impact of Covid-19, allowing a return to normal economic activities much earlier than in neighboring countries. However, the implications of certain policies related to economic resilience and health system capacity cannot yet be fully evaluated and may even prove to have negative impacts into the future., (© 2020 Fellowship of Postgraduate Medicine. Published by Elsevier Ltd.)

There is solid evidence for an association between physical activity and metabolic health outcomes in children and youth, but for methodological reasons most studies describe the intensity spectrum using only a few summary measures. We aimed to determine the multivariate physical activity intensity signature associated with metabolic health in a large and diverse sample of children and youth, by investigating the association pattern for the entire physical intensity spectrum. We used pooled data from 11 studies and 11,853 participants aged 5.8-18.4 years included in the International Children's Accelerometry Database. We derived 14 accelerometry-derived (ActiGraph) physical activity variables covering the intensity spectrum (from 0-99 to ≥8000 counts per minute). To handle the multicollinearity among these variables, we used multivariate pattern analysis to establish the associations with indices of metabolic health (abdominal fatness, insulin sensitivity, lipid metabolism, blood pressure). A composite metabolic health score was used as the main outcome variable. Associations with the composite metabolic health score were weak for sedentary time and light physical activity, but gradually strengthened with increasing time spent in moderate and vigorous intensities (up to 4000-5000 counts per minute). Association patterns were fairly consistent across sex and age groups, but varied across different metabolic health outcomes. This novel analytic approach suggests that vigorous intensity, rather than less intense activities or sedentary behavior, are related to metabolic health in children and youth., (Copyright © 2020. Published by Elsevier Inc.)

The concept of lifetime radiation risk of stochastic detrimental health outcomes is important in contemporary radiation protection, being used either to calculate detriment-weighted effective dose or to express risks following radiation accidents or medical uses of radiation. The conventionally applied time-integrated risks of radiation exposure are computed using average values of current population and health statistical data that need to be projected far into the future. By definition, the lifetime attributable risk (AR) is an approximation to more general lifetime risk quantities and is only valid for exposures under 1 Gy. The more general quantities, such as excess lifetime risk (ELR) and risk of exposure-induced cancer, are free of dose range constraints, but rely on assumptions concerning the unknown total radiation effect on demographic and health statistical data, and are more computationally complex than AR. Consideration of highly uncertain competing risks for other radiation-attributed outcomes are required in appropriate assessments of time-integrated risks of specific outcomes following high-dose (>1 Gy) exposures, causing non-linear dose responses in the resulting ELR estimate.Being based on the current population and health statistical data, the conventionally applied time-integrated risks of radiation exposure are: (i) not well suited for projections many years into the future because of the large uncertainties in future secular trends in the population-specific disease rates; and (ii) not optimal for application to atypical groups of exposed persons not well represented by the general population. Specifically, medical patients are atypical in this respect because their prospective risks depend strongly on the original diagnosis, the treatment modality, general cure rates, individual radiation sensitivity, and genetic predisposition. Another situation challenging the application of conventional risk quantities is a projection of occupational radiation risks associated with space flight, both due to higher radiation doses and astronauts' generally excellent health condition due to pre-selection, training, and intensive medical screening.An alternative quantity, named 'radiation-attributed decrease of survival' (RADS), known in past general statistical literature as 'cumulative risk', is recommended here for applications in space and medicine to represent the cumulative radiation risk conditional on survival until a certain age. RADS is only based on the radiation-attributed hazard rendering an insensitivity to competing risks or projections of current population statistics far into the future. Therefore, RADS is highly suitable for assessing semi-personalised radiation risks after radiation exposures from space missions or medical applications of radiation.

Fungi are an important part of the microbiota in healthy barrier tissues. Fungal dysbiosis in turn is associated with local and distal inflammatory diseases. Recent advances have shed light on the antigen-specific IL-17-dependent mechanisms that regulate fungal commensalism and prevent fungal overgrowth during homeostasis. Progress in our understanding of species-specific differences in fungus-host interactions provides new hypotheses of why Candida albicans-targeting T cells exceed those directed against other fungal species in the human T cell repertoire. Importantly, C. albicans-specific Th17 cells can also contribute to immune pathology in distant organs such as the lung via cross-reaction with heterologous antigens., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: The object of this study was to present the surgical results of a large, single-surgeon consecutive series of patients who had undergone transcisternal (TCi) or transcallosal-transventricular (TCTV) endoscope-assisted microsurgery for thalamic lesions., Methods: This is a retrospective study of a consecutive series of patients harboring thalamic lesions and undergoing surgery at one institution between February 2007 and August 2019. All surgical and patient-related data were prospectively collected. Depending on the relationship between the lesion and the surgically accessible thalamic surfaces (lateral ventricle, velar, cisternal, and third ventricle), one of the following surgical TCi or TCTV approaches was chosen: anterior interhemispheric transcallosal (AIT), posterior interhemispheric transtentorial subsplenial (PITS), perimedian supracerebellar transtentorial (PeST), or perimedian contralateral supracerebellar suprapineal (PeCSS). Since January 2018, intraoperative MRI has also been part of the protocol. The main study outcome was extent of resection. Complete neurological examination took place preoperatively, at discharge, and 3 months postoperatively. Descriptive statistics were calculated for the whole cohort., Results: In the study period, 92 patients underwent surgery for a thalamic lesion: 81 gliomas, 6 cavernous malformations, 2 germinomas, 1 metastasis, 1 arteriovenous malformation, and 1 ependymal cyst. In none of the cases was a transcortical approach adopted. Thirty-five patients underwent an AIT approach, 35 a PITS, 19 a PeST, and 3 a PeCSS. The mean follow-up was 38 months (median 20 months, range 1-137 months). No patient was lost to follow-up. The mean extent of resection was 95% (median 100%, range 21%-100%), and there was no surgical mortality. Most patients (59.8%) experienced improvement in their Karnofsky Performance Status. New permanent neurological deficits occurred in 8 patients (8.7%). Early postoperative (< 3 months after surgery) problems in CSF circulation requiring diversion occurred in 7 patients (7.6%; 6/7 cases in patients with high-grade glioma)., Conclusions: Endoscope-assisted microsurgery allows for the removal of thalamic lesions with acceptable morbidity. Surgeons must strive to access any given thalamic lesion through one of the four accessible thalamic surfaces, as they can be reached through either a TCTV or TCi approach with no or minimal damage to normal brain parenchyma. Patients harboring a high-grade glioma are likely to develop a postoperative disturbance of CSF circulation. For this reason, the AIT approach should be favored, as it facilitates a microsurgical third ventriculocisternostomy and allows intraoperative MRI to be done.

Previous studies indicate that many consumers eat rare hamburgers and that information about microbiological hazards related to undercooked meat does not necessarily lead to changed behavior. With this study we aim to investigate whether consumers' willingness to eat hamburgers, both risky and safe, depends on the situation where they are confronted with the food. A representative sample of 1046 Norwegian consumers participated in a web experiment. Participants were randomly divided into four groups. Each group was told to imagine a specific eating situation (at their friend's place, at home, at a restaurant abroad, at a domestic restaurant). Four pictures of hamburgers (rare, medium rare, medium, well-done) were presented in randomized order, and participants rated their intentions to eat each hamburger. Situated risk perception was measured as the stated likelihood of food poisoning from consuming hamburgers in eight different situations. The results show that both risk perception and risk taking vary depending on the situation. In general, participants perceive their own home to be the safest place to consume a hamburger, but they are significantly more likely to consume an undercooked hamburger when at a friend's place. These findings indicate that situations play an important role for consumers' likelihood of eating unsafe food, and that risk taking does not always follow risk perception. That risk taking is elevated in situations that may have social consequences should be taken into consideration when developing food safety strategies., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Listeria monocytogenes is a foodborne pathogen whose biofilm formation and desiccation tolerance may contribute to its survival in the food industry. L. monocytogenes possesses three cold-shock domain family proteins (CspA, CspB and CspD) known to be essential for adaptation against various food-relevant stress conditions including cold growth. The role of Csps in desiccation tolerance and biofilm formation was investigated in csp mutants as well as twenty-one other wild-type (WT) strains. Mutants with a single (ΔcspA) or multiple (ΔcspAB, ΔcspAD and ΔcspABD) deletions of csp genes, in a desiccation sensitive WT background (L. monocytogenes EGD-e) were immotile and exhibited an elevated desiccation tolerance compared to the parent strain. However, deletion of cspA in the more desiccation resistant food and outbreak related L. monocytogenes strains 568 and 08-5578 had no impact on desiccation tolerance although compared to the parent strains the mutants were also immotile. A correlation between lower motility and higher desiccation tolerance was observed among the 20 WT strains (Spearman rank correlation, r s  = -0.56, p = 0.01), although exceptions occurred indicating that multiple factors influence the diverse desiccation tolerance among L. monocytogenes strains. Expression of cspA was upregulated in WT EGD-e, 568 and 08-5578 strains after desiccation for seven days, while the 568 and 08-5578 ΔcspA mutants expressed elevated levels of cspD and cspB (>30 fold higher) compared to their WTs. This indicates that upregulation of the other csps compensates for the deleted cspA gene. Although biofilm formation was improved in all EGDe csp mutants relative to the WT strain, the opposite was observed for 568 and 08-5578 WT strains and their cspA deletion mutants. Only motile strains formed biofilm in the peg lid assay but a significant negative correlation (r s  = -0.60, p = 0.01) was seen between higher motility and higher biofilm formation of WT strains. In conclusion, the survival of L. monocytogenes strains in the food processing environment may depend on the control of motility, which is a necessity for biofilm formation but disadvantageous for desiccation survival., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Clinicians can encounter sex and gender disparities in diagnostic and therapeutic responses. These disparities are noted in epidemiology, pathophysiology, clinical manifestations, disease progression, and response to treatment. This Review discusses the fundamental influences of sex and gender as modifiers of the major causes of death and morbidity. We articulate how the genetic, epigenetic, and hormonal influences of biological sex influence physiology and disease, and how the social constructs of gender affect the behaviour of the community, clinicians, and patients in the health-care system and interact with pathobiology. We aim to guide clinicians and researchers to consider sex and gender in their approach to diagnosis, prevention, and treatment of diseases as a necessary and fundamental step towards precision medicine, which will benefit men's and women's health., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background . The relative rarity of ischemic compared with traumatic spinal cord injury (SCI) has limited a comparison of the outcomes of these conditions. Objective . To investigate the neurological and functional recovery of ischemic compared with traumatic acute SCI. Methods . Data were derived from the European Multicenter Study Spinal Cord Injury database. Patients with ischemic (iSCI) or traumatic SCI (tSCI), aged 18 years or older were evaluated at different time points from incidence: at about 1 month, 3 months, and 6 months. The neurological status was assessed at each time point by the International Standards for Neurological Classification of Spinal Cord Injury and the functional status by the Spinal Cord Independence Measure. Walking ability was evaluated by Walking Index for Spinal Cord Injury, 10-Meter Walk Test, and 6-Minute Walk Test. Because of the imbalances of the 2 groups in respect to size and lesion severity, a matching procedure according to age, neurological level, and severity of injury was performed. Outcomes evaluation was performed by means of a 2-way repeated-measures ANOVA. Results . The matching procedure resulted in 191 pairs. Both groups significantly improved from about 15 days after the lesion to 6 months. No differences were found in the course of neurological and functional recovery of iSCI compared with tSCI. Conclusions . This analysis from a representative cohort of participants revealed that from 15 days following the cord damage onward, the outcomes after iSCI and tSCI are comparable. This finding supports the potential enrolment of patients with acute iSCI into clinical trials from that point in time after the event and an evaluation up to 6 months afterward.

Background: Compared with troponin T/I test, the introduction of a high-sensitive (hs) troponin test may result in a higher proportion of positive test results in patients with chest pain and over-testing in patients without acute coronary syndrome. We assessed the impact of the introduction of the hs-troponin assay on the discharge diagnoses and the number of diagnostic tests in patients presenting with chest pain in a real-life setting in an emergency department., Methods: Retrospective chart review of patients presenting with chest pain to one of the largest hospitals in Switzerland. We compared the standard troponin period (December 2009 to November 2010) with the hs-troponin period (December 2010 to December 2011)., Results: Data from 1274 patients (standard 597 [46.9%], hs-troponin 677 [53.1%]) were analyzed. The proportion of patients with non-ST-segment elevation myocardial infarction increased (hs-troponin 14.9%, compared with 9.7%); the proportion in unstable angina (1.5% to 4.0%) and other cardiac illnesses (8.1% to 11.7%) decreased. Although the proportion of noncardiac chest pain illnesses (67%) remained unchanged, the proportion of positive hs-troponin was higher (6.1% vs 2.0%). The average number of additional tests/person decreased in troponin-positive patients (2.0 to 1.7 test per patient; P = .02) and troponin-negative patients (3.1 to 2.8 tests; P < .0001)., Conclusion: Although the introduction of the hs-troponin test resulted in a higher proportion of positive hs-troponin tests in patients with noncardiac chest pain, the average number of diagnostic tests decreased in patients with chest pain presenting to an emergency department, indicating an increased confidence of clinicians in their diagnosis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To describe low-field MRI findings associated with lumbosacral foraminal stenosis and radiculopathy and correlate these with clinical signs., Study Design: Retrospective study., Animals: Client-owned dogs (n = 240) that underwent a clinical examination and standardized MRI protocol of the lumbosacral junction., Methods: Medical records of dogs with degenerative lumbosacral stenosis with neurological clinical evaluation and MRI of the lumbosacral junction were used to describe imaging pathologies and relate them to clinical status., Results: In total, 480 L7 neuroforamina were evaluated. A loss of foraminal fat signal was identified in 364 of 480 neuroforamina of which 87.9% (n=320) showed also concurrent nerve root changes. Magnetic resonance imaging features of L7 radiculopathy included nerve root enlargement and hyperintensity to surrounding connective tissue in dorsal oblique gradient echo short time inversion recovery sequences and specific changes in shape, size, or position of the nerve root in transverse T1-weighted sequences. Radiculopathy was noted as a consequence of either circumferential (entrapment) or focal (impingement) foraminal stenosis. Lateral vertebral spondylotic and intervertebral facet joint changes were the most common underlying spinal and neuroforaminal pathologies. Clinical signs were present in the ipsilateral hind leg in 85% (n = 65) of dogs with unilateral lumbosacral imaging findings., Conclusion: A loss of foraminal fat signal was likely to be associated with L7 radiculopathy and foraminal stenosis. Unilateral lesions were generally associated with clinical signs on the ipsilateral limb., Clinical Significance: Loss of foraminal fat signal revealed by low-field MRI should prompt the assessment of concurrent radiculopathy and underlying stenosis, and in coherence with clinical findings, when is combined with clinical findings, improves the diagnosis of lumbosacral foraminal stenosis., (© 2020 The American College of Veterinary Surgeons.)

Background: A substantial proportion of echinococcosis transmission to humans via contamination of food has been assumed. However, the relative importance of food as a transmission vehicle has previously been estimated through expert opinion rather than empirical data., Objective: To find and evaluate empirical data that could be used to estimate the source attribution of echinococcosis, in particular the proportion that is transmitted through contaminated food., Methods: A systematic review was undertaken to identify reports on the risk factors for human cystic (CE) and alveolar (AE) echinococcosis. Data bases searched included PubMed, Scopus, Web of Knowledge, Cab Direct, Science Direct, Google Scholar, eLIBRARY.RU, CyberLeninka, CNKI and VIP. Search terms included Echinococc*, hydatid, epidemiology, logistic regression, risk factors, odds ratio, relative risk, risk factors. Reports, including grey literature where available, that had suitable data were selected and data were extracted. The main pathways of transmission were hypothesised to be contact with the definitive host, contaminated water, contaminated food and contaminated environment (other than food). For each study the attributable fraction for these potential sources of infection was calculated from the data presented. A meta-analysis was then undertaken to obtain pooled estimates for the relative contribution of these transmission pathways., Results: Data from 28 cross-sectional studies and 14 case-control studies were extracted. There was strong evidence for transmission by direct contact with dogs for both CE and AE. The estimated attributable fractions were 26.1% (CI 13.8%-39.6%) and 34.4% (CI 20.7% -48.2%) respectively. Transmission through contaminated water was estimated to be responsible for approximately 29.4% (CI 12.1%-51.7%) for CE and 24.8% (CI 10.6% to 42.6%) for AE. Contaminated food may be responsible for approximately 23.4% of CE cases (CI 2.1%-47.3%). Globally, there was insufficient evidence to conclude AE can be transmitted by food, although case control studies from low human incidence areas suggested that possibly 32.5% (CI 10.0%-53.2%) could be transmitted by food. There was also insufficient evidence that direct contact with foxes was a significant source of human disease. There were no suitable studies with a risk of environmental contact reported, but the residual attributable fraction thatwould likely include this pathway was approximately 21.1% for CE and 11.1% for AE., Conclusions: The results support the hypothesis that dog contact and drinking contaminated water are major pathways of transmission of both CE and AE. For contaminated food, the results are less consistent, but suggest that it is an important transmission pathway and provide better evidence than expert elicitations as previously used., Competing Interests: The authors have declared that no competing interests exist.

Aims: Atrial fibrillation (AF) and atrial flutter (AFL) are two of the most common atrial arrhythmias and often coexist. Many patients with AF or AFL are symptomatic, which impacts their quality of life (QoL). The purpose of this study was to determine whether coexistent AFL represents an added burden for AF patients., Methods: We combined baseline data from two large prospective, observational, multicenter cohort studies (BEAT-AF and Swiss-AF). All 3931 patients included in this analysis had documented AF. We obtained information on comorbidities, medication, and lifestyle factors . All participants had a clinical examination and a resting ECG. Symptom burden and QoL at the baseline examination were compared between patients with and without coexistent AFL using multivariable adjusted regression models., Results: Overall, 809 (20.6%) patients had a history of AFL. Patients with coexistent AFL more often had history of heart failure (28% vs 23%, p = 0.01), coronary artery disease (30% vs 26%, p = 0.007), failed therapy with antiarrhythmic drugs (44% vs 29%, p < 0.001), and more often underwent AF-related interventions (36% vs 17%, p < 0.001). They were more often symptomatic (70% vs 66%, p = 0.04) and effort intolerant (OR: 1.14; 95% CI: 1.01-1.28; p = 0.04). Documented AFL on the baseline ECG was associated with more symptoms (OR: 2.30; 95% CI: 1.26-4.20; p = 0.007)., Conclusion: Our data indicates that patients with coexistent AF and AFL are more often symptomatic and report poorer quality of life compared to patients suffering from AF only., (© 2020 The Authors.)

Increasing evidence suggests that interference with growth factor receptor tyrosine kinase (RTK) signaling can affect DNA damage response (DDR) networks, with a consequent impact on cellular responses to DNA-damaging agents widely used in cancer treatment. In that respect, the MET RTK is deregulated in abundance and/or activity in a variety of human tumors. Using two proteomic techniques, we explored how disrupting MET signaling modulates global cellular phosphorylation response to ionizing radiation (IR). Following an immunoaffinity-based phosphoproteomic discovery survey, we selected candidate phosphorylation sites for extensive characterization by targeted proteomics focusing on phosphorylation sites in both signaling networks. Several substrates of the DDR were confirmed to be modulated by sequential MET inhibition and IR, or MET inhibition alone. Upon combined treatment, for two substrates, NUMA1 S395 and CHEK1 S345, the gain and loss of phosphorylation, respectively, were recapitulated using invivo tumor models by immunohistochemistry, with possible utility in future translational research. Overall, we have corroborated phosphorylation sites at the intersection between MET and the DDR signaling networks, and suggest that these represent a class of proteins at the interface between oncogene-driven proliferation and genomic stability., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Objective: The "chopsticks" technique is a 3-instrument, 2-hand mononostril technique that has been recently introduced in endoscopic neurosurgery. It allows a dynamic surgical view controlled by one surgeon only while keeping bimanual dissection. Being a mononostril approach, it requires manipulation of the mucosa of one nasal cavity only. The rationale of the technique is to reduce nasal morbidity without compromising surgical results and complication rates. There are, however, no data available on its results in endoscopic surgery (transsphenoidal surgery [TSS]) for pituitary adenoma., Methods: The authors performed a cohort analysis of prospectively collected data on 144 patients (156 operations) undergoing TSS using the chopsticks technique with 3T intraoperative MRI. All patients had at least 3 months of postoperative neurosurgical, endocrinological, and rhinological follow-up (Sino-Nasal Outcome Test-20 [SNOT-20] and Sniffin' Sticks). The surgical technique is described, and the achieved gross-total resection (GTR) and extent of resection (EOR) together with patients' clinical outcomes and complications are descriptively reported., Results: On 3-month postoperative MRI, GTR was achieved in 71.2% of patients with a mean EOR of 96.7%. GTR was the surgical goal in 122 of 156 cases and was achieved in 106 of 122 (86.9%), with a mean EOR of 98.7% (median 100%, range 49%-100%). There was no surgical mortality. At a median follow-up of 15 months (range 3-70 months), there was 1 permanent neurological deficit. As of the last available follow-up, 11.5% of patients had a new pituitary single-axis deficit, whereas 26.3% had improvement in endocrinological function. Three patients had new postoperative hyposmia. One patient had severe impairment of sinonasal function (SNOT-20 score > 40). The operation resulted in endocrine remission in 81.1% of patients with secreting adenomas., Conclusions: This study shows that the chopsticks technique confers resection and morbidity results that compare favorably with literature reports of TSS. This technique permits a single surgeon to perform effective endoscopic bimanual dissection through a single nostril, reducing manipulation of healthy tissue and thereby possibly minimizing surgical morbidity.

Statement of Problem: Interim dental restorations can be fabricated by using additive manufacturing (AM) technologies. Although dental restoration contours can be easily and accurately fabricated by using computer-aided design (CAD) procedures, protocols for creating predictable color dimensions of AM interim restorations are lacking., Purpose: The purpose of this in vitro study was to measure and compare color dimensions of different AM and conventional interim restorative materials., Material and Methods: Disks (N=420) were fabricated by using either conventionally (CNV group) or additively manufactured (AM group) materials. The CNV group was further divided into the subgroups CNV-1 (Protemp 4; 3M ESPE) and CNV-2 (Anaxdent new outline dentin; Anaxdent). AM subgroups included AM-1 (FreePrint temp; Detax), AM-2 (E-Dent 400; Envisiontec), AM-3 (NextDent C&B; NextDent), AM-4 (NextDent C&B MFH; NextDent), and AM-5 (Med620 VEROGlaze; Stratasys). Color measurements in the CIELab coordinates were made by using a spectrophotometer (VITA EasyShade Advance 4.0; VITA) with a standardized photography gray card as a background under room light conditions (1003 lux). Color difference (ΔE*) values were calculated by using the CIE76 and CIEDE2000 formulas. The data were analyzed by using the Kruskal-Wallis test with nonparametric pairwise comparisons., Results: Owing to a software error, the spectrophotometer was unable to measure the color of any specimens in the AM-5 subgroup, which was consequently excluded from further analysis. Significant differences (P=.001) between 2 manufacturing groups were found based on the L* variable. All subgroups were significantly different from each other for all 3 variables (P<.001). Pairwise comparisons revealed that all groups were significantly different from each other, except for the AM-1 and AM-2 subgroups, compared with the CNV-1 subgroup for the L* color dimension. The ΔE* values calculated by using the CIE76 formula varied from 6.63 to 23.1 and by using the CIEDE2000 formula from 3.43 to 10.21, suggesting a perceptible and unacceptable color mismatch between the CNV and AM groups., Conclusions: None of the additively manufactured interim materials tested matched the conventional interim materials in all 3 CIELab color dimensions., (Copyright © 2019 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.)

Heart failure (HF) phenotypes differ according to sex. HF preserved ejection fraction (EF) has a greater prevalence in women and HF reduced EF (HFrEF) in men. Women with HF survive longer than men and have a lower risk of sudden death. Ischemia is the most prominent cause in men, whereas hypertension and diabetes contribute to a greater extent in women. Women with HF have a greater stiffness of the smaller left ventricle and a higher EF than men. This higher stiffness of women's hearts may be based on an increase in fibrosis at old age. In younger women estrogen reduces collagen production in female cardiac fibroblasts, but stimulates it in males. Lipid and energy metabolism is better maintained in female than in male stressed hearts. Pulse pressure is a key determinant of outcome in HF women but not in men. Takotsubo and peripartum cardiomyopathy are rare diseases affecting predominantly or exclusively women. Sudden cardiac arrest affects more men than women, but women are less adequately treated. New findings in HF therapy indicate that women with HFrEF need lower doses of beta-blockers and angiotensin-converting enzyme inhibitors than men for optimal effects. The combined neprilysin inhibitor/angiotensin II receptor blockers sacubitril-valsartan led to a significant reduction in event rate versus valsartan in women, which was not observed in men. Unfortunately, only less than 10% of recent randomized controlled trial report effects and adverse drug reactions for women and men separately. More research on sex differences in pathophysiology and therapy of HF is needed., Competing Interests: Conflict of Interest: The author has no financial conflicts of interest., (Copyright © 2020. Korean Society of Heart Failure.)

Slowing down translation in either the cytosol or the mitochondria is a conserved longevity mechanism. Here, we found a non-interventional natural correlation of mitochondrial and cytosolic ribosomal proteins (RPs) in mouse population genetics, suggesting a translational balance. Inhibiting mitochondrial translation in C. elegans through mrps-5 RNAi repressed cytosolic translation. Transcriptomics integrated with proteomics revealed that this inhibition specifically reduced translational efficiency of mRNAs required in growth pathways while increasing stress response mRNAs. The repression of cytosolic translation and extension of lifespan from mrps-5 RNAi were dependent on atf-5/ATF4 and independent from metabolic phenotypes. We found the translational balance to be conserved in mammalian cells upon inhibiting mitochondrial translation pharmacologically with doxycycline. Lastly, extending this in vivo, doxycycline repressed cytosolic translation in the livers of germ-free mice. These data demonstrate that inhibiting mitochondrial translation initiates an atf-5/ATF4-dependent cascade leading to coordinated repression of cytosolic translation, which could be targeted to promote longevity., Competing Interests: Declaration of Interests R.H.H. is an inventor on a patent related to mitochondrial ribosomal proteins as aging regulators. The other authors declare that they have no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)