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The text reconstructs the concepts of practice and practicality used in ethnomethodology and conversation analysis and examines their internal similarities and differences as well as similarities and differences to other practice theories. After a description of the characteristics of practice theories, the ethnomethodological perspective on practice and practicality is presented. Then, the use of the terms in conversation analysis is examined. Ethnomethodology uses the notions of “practice” and “practicality” to outline a non-metaphysical theory of social order in which the sharedness of rules or meanings is not presupposed. “Practical” here means that social action, and social order more generally, are practically grounded as well as temporally and situationally constrained. The fact that practical action is fundamentally situated and can only be understood “from within” establishes an essentially indexical character of practical action. In conversation analysis, “practices” are viewed as “context-free” but “context-sensitive” components that constitute action and as such become the objects of investigation. While some have diagnosed a departure of conversation analysis from its ethnomethodological roots, I argue that “context-freeness” and “context-sensitivity” should be complemented by “context-productivity” by reference to Garfinkel’s interpretation of Aron Gurwitsch’s gestalt phenomenology in order to formulate a more encompassing concept of practice.

Die Cargo Sous Terrain AG plant, die wichtigsten Logistikzentren des Mittellands mit einem automatisierten unterirdischen Gütertransport miteinander zu verbinden. Die erste zum Bau vorgesehene Teilstrecke führt durch die drei Kantone Solothurn, Aargau und Zürich. Zwar schafft das Bundesgesetz über den unterirdischen Gütertransport (UGüTG) einen spezifischen Rechtsrahmen samt bundesrechtlicher Sachplanung und Plangenehmigung. Offen bleibt allerdings, inwieweit die sehr unterschiedliche kantonale Vollzugspraxis beim Grundwasserschutz auf die entsprechenden Verfahren einwirkt. Eine Auslegung der einschlägigen Normen legt nahe, dass der Bund mit dem UGüTG die kantonalen Eigenheiten im Vollzug erheblich überlagert. -- La société Cargo Sous Terrain AG prévoit de connecter les principaux centres logistiques de la région du Plateau suisse via un réseau de transport de marchandises automatisé et souterrain. La première section de ce projet traversera les cantons de Soleure, d'Argovie et de Zurich. La loi fédérale sur le transport souterrain de marchandises (LTSM) fournit un cadre juridique spécifique pour la planification sectorielle et l'approbation des plans conformément au droit fédéral. Toutefois, l'impact des pratiques d'exécution, qui varient considérablement d'un canton à l'autre en matière de protection des eaux souterraines, reste à évaluer. Une interprétation des normes pertinentes suggère que la Confédération, par le biais de la LTSM, supplante sensiblement les spécificités cantonales en matière d'exécution.

Abstract Objective We aimed to assess the effect of SGLT2i on arrhythmias by conducting a meta-analysis using data from randomized controlled trials(RCTs). Background Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have shown cardioprotective effects via multiple mechanisms that may also contribute to decrease arrhythmias risk. Methods We searched in databases (PubMed, Embase, Cochrane Library, and clinicaltrials.gov) up to April 2023. RCTs comparing SGLT2i with placebo were included. The effects of SGLT2i on atrial fibrillation(AF), atrial flutter(AFL), composite AF/AFL, ventricular fibrillation(VF), ventricular tachycardia(VT), ventricular extrasystoles(VES), sudden cardiac death(SCD) and composite VF/VT/SCD were evaluated. Results 33 placebo-controlled RCTs were included, comprising 88,098 patients (48,585 in SGLT2i vs. 39,513 in placebo). The mean age was 64.9 ± 9.4 years, 63.0% were male. The mean follow-up was 1.4 ± 1.1 years. The pooled-results showed that SGLT2i was associated with a significantly lower risk of AF [risk ratio(RR): 0.88, 95% confidence interval(CI) 0.78–1.00, P = 0.04] and composite AF/AFL (RR: 0.86, 95%CI 0.77–0.96, P = 0.01). This favorable effect appeared to be substantially pronounced in patients with HFrEF, male gender, dapagliflozin, and > 1 year follow-up. For SCD, only in heart failure patients, SGLT2i were found to be associated with a borderline lower risk of SCD (RR: 0.67, P = 0.05). No significant effects of SGLT2i on other ventricular arrhythmic outcomes were found. Conclusions SGLT2i lowers the risks of AF and AF/AFL, and this favorable effect appeared to be particularly pronounced in patients with HFrEF, male gender, dapagliflozin, and longer follow-up (> 1 year). SGLT2i lowers the risk of SCD only in heart failure patients. Graphical Abstract

Background/Objectives: The diagnosis of lung carcinoma (LC) is currently performed in small biopsies and according to the WHO classification by using limited stains to spare tissue for molecular testing. This procedure, however, often causes diagnostic uncertainty among pathologists. Methods: In this retrospective analysis, we compared the diagnosis made by these guidelines in 288 lung biopsies with that using more stains, as retrieved from our archive. We also compared the results of p63 and p40 immunoexpression and investigated the diagnostic role of p53/Rb1. Results: In our investigation, we reached a definite diagnosis with a mean number of one stain compared with six stains in the original diagnostic procedure, with a 97.3% concordance rate. Only in the case of metastases, a clear advantage is proven in the use of more stains, especially in the absence of clinical information. We also found a comparable utility of p40 and p63 for the diagnosis of squamous cell carcinoma, despite the higher p63 expression in other histological types. Moreover, normal p53/Rb1 expression could be utilized for the exclusion of small-cell LC. Conclusions: Our study confirms the diagnostic certainty achieved by the suggestions of the WHO classification and justifies the potential insecurity in the absence of adequate communication with the treating clinician.

Introduction: Patients with metastatic NSCLC (mNSCLC) treated with immune checkpoint inhibitors in clinical practice may often not meet the strict inclusion criteria of clinical trials. Our aim was to assess the trial eligibility of patients with mNSCLC treated with pembrolizumab monotherapy in real-world and to compare the outcome of “trial-ineligible” and “potentially trial-eligible” patients. Methods: Data from the prospective, clinical research platform CRISP were used to compare patient characteristics, treatment, and outcome of patients with programmed cell death-ligand 1 tumor proportion score greater than or equal to 50% tumors treated with pembrolizumab monotherapy who are deemed either “potentially trial-eligible” or “trial-ineligible” according to inclusion and exclusion criteria of the registrational studies (KEYNOTE-024 and -042). Results: Of 746 patients included, 343 patients (46.0%) were classified as “trial-ineligible” and had significantly worse outcomes compared with “potentially trial-eligible” patients (n = 403, 54.0%): median progression-free survival: 6.2 (95% confidence interval [CI]: 5.2–8.4) versus 10.3 (95% CI: 8.4–13.8) months, hazard ratio (trial-ineligible versus potentially trial-eligible) of 1.43 (95% CI: 1.19–1.72), p less than 0.001; median overall survival: 15.9 (95% CI: 11.4–20.3) versus 25.3 (95% CI: 19.8–30.4) months, hazard ratio of 1.36 (95% CI: 1.10–1.67), p equals 0.004. Conclusions: Our data reveal that a considerable proportion of patients with mNSCLC are not eligible to participate in a clinical trial and were found to have worse outcomes than potentially trial-eligible patients, whose outcomes were comparable with those obtained from pivotal clinical trials. This is of substantial clinical relevance for physicians discussing outcomes to be expected with their patients and stresses the need for real-world effectiveness analyses.

Abstract Mortality is predicted by the sum of behavior-related health risk factors (BRFs: tobacco smoking, alcohol drinking, body overweight, and physical inactivity). We analyzed degrees and combinations of BRFs in their relation to mortality and adjusted for mental disorders. In a random sample of the general population in northern Germany aged 18–64, BRFs and mental disorders had been assessed in 1996–1997 by the Munich Composite International Diagnostic Interview. A sum score including eight ranks of the behavior-related health risk factors was built. Death and its causes were ascertained 2017–2018 using residents’ registration files and death certificates. Relations of the sum score and combinations of the BRFs at baseline with all-cause, cancer, and cardiovascular mortality 20 years later were analyzed. The sum score and combinations predicted all-cause, cardiovascular and cancer mortality. The odds ratio of the sum score was 1.38 (95% confidence interval 1.31–1.46) after adjustment for age, gender, and mental disorder. In addition to the BRFs, mood, anxiety or somatoform disorders were not related to mortality. We concluded that the sum score and combinations of behavior-related health risk factors predicted mortality, even after adjustment for mental disorders.

Abstract History of syncope is an independent predictor for sudden cardiac death. Programmed stimulation may be considered for risk stratification, but data remain sparse among different populations. Here, we analyzed the prognostic value of inducible ventricular arrhythmia (VA) regarding clinical outcome in patients with syncope undergoing defibrillator implantation. Among 4196 patients enrolled in the prospective, multi-center German Device Registry, patients with syncope and inducible VA (n = 285, 6.8%) vs. those with a secondary preventive indication (n = 1885, 45.2%), defined as previously documented sustained ventricular tachycardia or ventricular fibrillation, serving as a control group were studied regarding demographics, device implantation and post-procedural adverse events. Patients with syncope and inducible VA (64.9 ± 14.4 years, 81.1% male) presented less frequently with congestive heart failure (15.1% vs. 29.1%; p

We developed an ELISPOT assay for evaluating Middle East respiratory syndrome coronavirus (MERS-CoV)‒specific T-cell responses in dromedary camels. After single modified vaccinia virus Ankara-MERS-S vaccination, seropositive camels showed increased levels of MERS-CoV‒specific T cells and antibodies, indicating suitability of camel vaccinations in disease-endemic areas as a promising approach to control infection.

BackgroundDespite the putatively targetable genomic landscape of high-grade gliomas, the long-term survival benefit of genomically-tailored targeted therapies remains discouraging.MethodsUsing glioblastoma (GBM) as a representative example of high-grade gliomas, we evaluated the clonal architecture and distribution of hotspot mutations in 388 GBMs from the Cancer Genome Atlas (TCGA). Mutations were matched with 54 targeted therapies, followed by a comprehensive evaluation of drug biochemical properties in reference to the drug’s clinical efficacy in high-grade gliomas. We then assessed clinical outcomes of a cohort of patients with high-grade gliomas with targetable mutations reviewed at the Johns Hopkins Molecular Tumor Board (JH MTB; n = 50).ResultsAmong 1,156 sequence alterations evaluated, 28.6% represented hotspots. While the frequency of hotspot mutations in GBM was comparable to cancer types with actionable hotspot alterations, GBMs harbored a higher fraction of subclonal mutations that affected hotspots (7.0%), compared to breast cancer (4.9%), lung cancer (4.4%), and melanoma (1.4%). In investigating the biochemical features of targeted therapies paired with recurring alterations, we identified a trend toward higher lipid solubility and lower IC50 in GBM cell lines among drugs with clinical efficacy. The drugs’ half-life, molecular weight, surface area and binding to efflux transporters were not associated with clinical efficacy. Among the JH MTB cohort of patients with IDH1 wild-type high-grade gliomas who received targeted therapies, trametinib monotherapy or in combination with dabrafenib conferred radiographic partial response in 75% of patients harboring BRAF or NF1 actionable mutations. Cabozantinib conferred radiographic partial response in two patients harboring a MET and a PDGFRA/KDR amplification. Patients with IDH1 wild-type gliomas that harbored actionable alterations who received genotype-matched targeted therapy had longer progression-free (PFS) and overall survival (OS; 7.37 and 14.72 respectively) than patients whose actionable alterations were not targeted (2.83 and 4.2 months respectively).ConclusionWhile multiple host, tumor and drug-related features may limit the delivery and efficacy of targeted therapies for patients with high-grade gliomas, genotype-matched targeted therapies confer favorable clinical outcomes. Further studies are needed to generate more data on the impact of biochemical features of targeted therapies on their clinical efficacy for high-grade gliomas.

Abstract Background ST-segment elevation myocardial infarction (STEMI) still causes significant mortality and morbidity despite best-practice revascularization and adjunct medical strategies. Within the STEMI population, there is a spectrum of higher and lower risk patients with respect to major adverse cardiovascular and cerebral events (MACCE) or re-hospitalization due to heart failure. Myocardial and systemic metabolic disorders modulate patient risk in STEMI. Systematic cardiocirculatory and metabolic phenotyping to assess the bidirectional interaction of cardiac and systemic metabolism in myocardial ischemia is lacking. Methods Systemic organ communication in STEMI (SYSTEMI) is an all-comer open-end prospective study in STEMI patients > 18 years of age to assess the interaction of cardiac and systemic metabolism in STEMI by systematically collecting data on a regional and systemic level. Primary endpoint will be myocardial function, left ventricular remodelling, myocardial texture and coronary patency at 6 month after STEMI. Secondary endpoint will be all-cause death, MACCE, and re-hospitalisation due to heart failure or revascularisation assessed 12 month after STEMI. The objective of SYSTEMI is to identify metabolic systemic and myocardial master switches that determine primary and secondary endpoints. In SYSTEMI 150–200 patients are expected to be recruited per year. Patient data will be collected at the index event, within 24 h, 5 days as well as 6 and 12 months after STEMI. Data acquisition will be performed in multilayer approaches. Myocardial function will be assessed by using serial cardiac imaging with cineventriculography, echocardiography and cardiovascular magnetic resonance. Myocardial metabolism will be analysed by multi-nuclei magnetic resonance spectroscopy. Systemic metabolism will be approached by serial liquid biopsies and analysed with respect to glucose and lipid metabolism as well as oxygen transport. In summary, SYSTEMI enables a comprehensive data analysis on the levels of organ structure and function alongside hemodynamic, genomic and transcriptomic information to assess cardiac and systemic metabolism. Discussion SYSTEMI aims to identify novel metabolic patterns and master-switches in the interaction of cardiac and systemic metabolism to improve diagnostic and therapeutic algorithms in myocardial ischemia for patient-risk assessment and tailored therapy. Trial registration Trial Registration Number: NCT03539133

Abstract Malignant ventricular arrhythmias (VA) after acute myocardial infarction remain a major threat. Aim of this study was to characterize the electrophysiological and autonomic sequelae of cardiac ischemia and reperfusion (I/R) in mice during the first week post incident. Left ventricular function was serially assessed using transthoracic echocardiography. VA were quantified by telemetric electrocardiogram (ECG) recordings and electrophysiological studies on the 2nd and 7th day after I/R. Cardiac autonomic function was evaluated by heart rate variability (HRV) and heart rate turbulence (HRT). Infarct size was quantified by planimetric measures. I/R caused significant myocardial scarring and diminished left ventricular ejection fraction. The ECG intervals QRS, QT, QTc, and JTc were prolonged in I/R mice. Both spontaneous VA scored higher and the inducibility of VA was raised in I/R mice. An analysis of HRV and HRT indicated a relative reduction in parasympathetic activity and disturbed baroreflex sensitivity up to 7 days after I/R. In summary, during the first week after I/R, the murine heart reflects essential features of the human heart after myocardial infarction, including a greater vulnerability for VA and a decreased parasympathetic tone accompanied by decelerated depolarization and repolarization parameters.

The sudden emergence of SARS-CoV-2 demonstrates the need for new vaccines that rapidly protect in the case of an emergency. In this study, we developed a recombinant MVA vaccine co-expressing SARS-CoV-2 prefusion-stabilized spike protein (ST) and SARS-CoV-2 nucleoprotein (N, MVA-SARS-2-ST/N) as an approach to further improve vaccine-induced immunogenicity and efficacy. Single MVA-SARS-2-ST/N vaccination in K18-hACE2 mice induced robust protection against lethal respiratory SARS-CoV-2 challenge infection 28 days later. The protective outcome of MVA-SARS-2-ST/N vaccination correlated with the activation of SARS-CoV-2-neutralizing antibodies (nABs) and substantial amounts of SARS-CoV-2-specific T cells especially in the lung of MVA-SARS-2-ST/N-vaccinated mice. Emergency vaccination with MVA-SARS-2-ST/N just 2 days before lethal SARS-CoV-2 challenge infection resulted in a delayed onset of clinical disease outcome in these mice and increased titers of nAB or SARS-CoV-2-specific T cells in the spleen and lung. These data highlight the potential of a multivalent COVID-19 vaccine co-expressing S- and N-protein, which further contributes to the development of rapidly protective vaccination strategies against emerging pathogens.

Ein demokratischer Rechtsstaat wie die Schweiz muss rational handeln und sich dabei auch wissenschaftlichen Wissens bedienen. Der vorliegende Beitrag stellt Konzepte und Instrumente vor, um diesen Anforderungen gerecht zu werden, und beleuchtet deren normative Verankerung. Anhand des Verhältnismässigkeitsprinzips wird die Bedeutung wissenschaftlicher Rationalität als Garantin rationalen Staatshandelns näher untersucht und gezeigt, dass die entsprechenden rechtlichen Strukturen teilweise nicht mehr adäquat sind. -- Un État de droit démocratique comme la Suisse est tenu d'agir rationnellement et doit, à cette fin, tenir compte des connaissances scientifiques existantes. Cet article présente les concepts et les instruments permettant de répondre à ces exigences et met en évidence leur ancrage normatif. L'importance de la rationalité scientifique en tant que garante d'une l'action rationnelle de l'État est examinée à la lumière du principe de proportionnalité. Il est en outre démontré que les structures juridiques concernées sont en partie obsolètes.

Abstract Background Missing data are ubiquitous in randomised controlled trials. Although sensitivity analyses for different missing data mechanisms (missing at random vs. missing not at random) are widely recommended, they are rarely conducted in practice. The aim of the present study was to demonstrate sensitivity analyses for different assumptions regarding the missing data mechanism for randomised controlled trials using latent growth modelling (LGM). Methods Data from a randomised controlled brief alcohol intervention trial was used. The sample included 1646 adults (56% female; mean age = 31.0 years) from the general population who had received up to three individualized alcohol feedback letters or assessment-only. Follow-up interviews were conducted after 12 and 36 months via telephone. The main outcome for the analysis was change in alcohol use over time. A three-step LGM approach was used. First, evidence about the process that generated the missing data was accumulated by analysing the extent of missing values in both study conditions, missing data patterns, and baseline variables that predicted participation in the two follow-up assessments using logistic regression. Second, growth models were calculated to analyse intervention effects over time. These models assumed that data were missing at random and applied full-information maximum likelihood estimation. Third, the findings were safeguarded by incorporating model components to account for the possibility that data were missing not at random. For that purpose, Diggle-Kenward selection, Wu-Carroll shared parameter and pattern mixture models were implemented. Results Although the true data generating process remained unknown, the evidence was unequivocal: both the intervention and control group reduced their alcohol use over time, but no significant group differences emerged. There was no clear evidence for intervention efficacy, neither in the growth models that assumed the missing data to be at random nor those that assumed the missing data to be not at random. Conclusion The illustrated approach allows the assessment of how sensitive conclusions about the efficacy of an intervention are to different assumptions regarding the missing data mechanism. For researchers familiar with LGM, it is a valuable statistical supplement to safeguard their findings against the possibility of nonignorable missingness. Trial registration The PRINT trial was prospectively registered at the German Clinical Trials Register (DRKS00014274, date of registration: 12th March 2018).

Aging is associated with a decline in immune system functionality. So-called immunosenescence may impair the successful vaccination of elderly people. Thus, improved vaccination strategies also suitable for an aged immune system are required. Modified Vaccinia virus Ankara (MVA) is a highly attenuated and replication-deficient vaccinia virus that has been established as a multipurpose viral vector for vaccine development against various infections. We characterized a recombinant MVA expressing a prefusion-stabilized version of SARS-CoV-2 S protein (MVA-ST) in an aged-hamster model for COVID-19. Intramuscular MVA-ST immunization resulted in protection from disease and severe lung pathology. Importantly, this protection was correlated with a potent activation of SARS-CoV-2 specific T-cells and neutralizing antibodies. Our results suggest that MVA vector vaccines merit further evaluation in preclinical models to contribute to future clinical development as candidate vaccines in elderly people to overcome the limitations of age-dependent immunosenescence.

Abstract Ultra-high-density (UHD) mapping can improve scar area detection and fast activation mapping in patients undergoing catheter ablation of ventricular tachycardia (VT). The aim of the present study was to compare the outcome after VT ablation guided by UHD and conventional point-by-point 3D-mapping. The acute and long-term ablation outcome of 61 consecutive patients with UHD mapping (64-electrode mini-basket catheter) was compared to 61 consecutive patients with conventional point-by-point 3D-mapping using a 3.5 mm tip catheter. Patients, whose ablation was guided by UHD mapping had an improved 24-months outcome in comparison to patients with conventional mapping (cumulative incidence estimate of the combination of recurrence or disease-related death of 52.4% (95% confidence interval (CI) [36.9–65.7]; recurrence: n = 25; disease-related death: n = 4) versus 69.6% (95% CI [55.9–79.8]); recurrence: n = 31; disease-related death n = 11). In a cause-specific Cox proportional hazards model, UHD mapping (hazard ratio (HR) 0.623; 95% CI [0.390–0.995]; P = 0.048) and left ventricular ejection fraction > 30% (HR 0.485; 95% CI [0.290–0.813]; P = 0.006) were independently associated with lower rates of recurrence or disease-related death. Other procedural parameters were similar in both groups. In conclusion, UHD mapping during VT ablation was associated with fewer VT recurrences or disease-related deaths during long-term follow-up in comparison to conventional point-by-point mapping. Complication rates and other procedural parameters were similar in both groups.

Abstract Background Vaccination against SARS-CoV-2 has been the main tool to contain the pandemic. The rush development of the 3 vaccines and their expedited approval have led to inoculation of millions of patients around the world, leading to a containment of the disease. Despite continuous viral mutations and the identification of weaker variants, the severity of the infections has been mild, with many patients being either asymptomatic or recovering at home. Currently the focus has shifted from the host of organ damage related to the infection to potential side effects of the vaccine. Myocarditis has been reported as one of the potential side effects from the mRNA vaccine, affecting young healthy individuals. Up to September 30, 2021, 1.243 cases of myocarditis after vaccination with BNT162b2 Comirnaty© were registered in young adults by the Paul-Ehrlich-Institute in Germany alone. The exact pathophysiology and the risk factors for myocarditis following vaccination remain unclear. We present a case series of eight patients with cardiac symptom shortly after SARS-CoV-2 mRNA vaccination (BNT162b6, Biontech, Comirnaty© or mRNA-1237 Moderna, Spikevax©). Patients and methods Eight patients between 13 and 56 years of age, vaccinated with either BNT162b2 or mRNA-1273 mRNA vaccine between January and August 2021 developed cardiac side effects shortly after either their first or second dose of the vaccine. Clinical data were retrieved from the clinical information system and analyzed. To support diagnosis of myocarditis or pericarditis, cardiac magnetic resonance imaging (MRI) was performed shortly after the onset of symptoms, with further investigations in severe cases. Symptoms were defined as dyspnea, chest pain and cardiac arrhythmia as determined by electrocardiography. Results Eight patients (5 males and 3 females) developed cardiac symptoms compatible with myocarditis, according to the CDC criteria, shortly after SARS-CoV-2 mRNA vaccination. Three patients (2 males, 1 female) required hospitalization due to severe chest pain and elevated troponin levels. All patients recovered fully within 7 days from the symptom onset. Conclusions Our data suggest that cardiac adverse events such as myocarditis or pericarditis shortly after SARS-CoV-2 mRNA vaccination are rare but possible and occur particularly in male patients.

Abstract The growing world population and global increases in the standard of living both result in an increasing demand for food, feed and other plant‐derived products. In the coming years, plant‐based research will be among the major drivers ensuring food security and the expansion of the bio‐based economy. Crop productivity is determined by several factors, including the available physical and agricultural resources, crop management, and the resource use efficiency, quality and intrinsic yield potential of the chosen crop. This review focuses on intrinsic yield potential, since understanding its determinants and their biological basis will allow to maximize the plant's potential in food and energy production. Yield potential is determined by a variety of complex traits that integrate strictly regulated processes and their underlying gene regulatory networks. Due to this inherent complexity, numerous potential targets have been identified that could be exploited to increase crop yield. These encompass diverse metabolic and physical processes at the cellular, organ and canopy level. We present an overview of some of the distinct biological processes considered to be crucial for yield determination that could further be exploited to improve future crop productivity.

The SARS-CoV-2 spike (S) glycoprotein is synthesized as a large precursor protein and must be activated by proteolytic cleavage into S1 and S2. A recombinant modified vaccinia virus Ankara (MVA) expressing native, full-length S protein (MVA-SARS-2-S) is currently under investigation as a candidate vaccine in phase I clinical studies. Initial results from immunogenicity monitoring revealed induction of S-specific antibodies binding to S2, but low-level antibody responses to the S1 domain. Follow-up investigations of native S antigen synthesis in MVA-SARS-2-S–infected cells revealed limited levels of S1 protein on the cell surface. In contrast, we found superior S1 cell surface presentation upon infection with a recombinant MVA expressing a stabilized version of SARS-CoV-2 S protein with an inactivated S1/S2 cleavage site and K986P and V987P mutations (MVA-SARS-2-ST). When comparing immunogenicity of MVA vector vaccines, mice vaccinated with MVA-SARS-2-ST mounted substantial levels of broadly reactive anti-S antibodies that effectively neutralized different SARS-CoV-2 variants. Importantly, intramuscular MVA-SARS-2-ST immunization of hamsters and mice resulted in potent immune responses upon challenge infection and protected from disease and severe lung pathology. Our results suggest that MVA-SARS-2-ST represents an improved clinical candidate vaccine and that the presence of plasma membrane–bound S1 is highly beneficial to induce protective antibody levels.

IntroductionSpace use patterns in fish result from the interactions between individual movement behaviour and characteristics of the environment. Herbivorous parrotfishes, for instance, are constrained by the availability of resources and different predation risks. The resulting spatial distribution of the fish population can strongly influence community composition and ecosystem resilience.MethodsIn a novel approach, we combine individual-based modelling (IBM) with an artificial potential field algorithm to realistically represent fish movements and the decision-making process. Potential field algorithms, which are popular methods in mobile robot path planning, efficiently generate the best paths for an entity to navigate through vector fields of repellent and attracting forces. In our model the repellent and attracting forces are predation risk and food availability, both implemented as separate grid-based vector fields. The coupling of individual fish bioenergetics with a navigation capacity provides a mechanistic basis to analyse how the habitat structure influences population dynamics and space utilization.ResultsModel results indicate that movement patterns and the resulting spatial distributions strongly depend on habitat fragmentation with the bioenergetic capacity to spawn and reproduce being particularly susceptible processes at the individual level. The resulting spatial distributions of the population are more irregularly distributed among coral reef patches the more the coral reef habitat becomes fragmented and reduced.DiscussionThis heterogeneity can have strong implications for the delivered ecosystem functioning, e.g., by concentrating or diluting the grazing effort. Our results also highlight the importance of incorporating individual foraging-path patterns and the spatial exploitation of microhabitats into marine spatial planning by considering the effects of fragmentation. The integration of potential fields into IBMs represents a promising strategy to advance our understanding of complex decision-making in animals by implementing a more realistic and dynamic decision-making process, in which each fish weighs different rewards and risks of the environment. This information may help to identify core areas and essential habitat patches and assist in effective marine spatial management.

The low level of the Jurassic sea in the area of Bad Essen-Barkhausen (Wiehen Mountains, NW Germany) was a precondition for the migration of a herd of sauropods and theropods through this coastal area about 153 million years ago. The dinosaurs left at least 11 trackways on a single fine-grained siltstone layer and several more footprints on another, younger layer. The dinosaur track layers experienced diagenesis and subsequent uplifting during the Late Cretaceous, so that they are presently exposed in sub-vertical position on a quarry rock wall. Since the discovery of the tracks in 1921, their preservation has been challenging. It has not been possible to recover the tracks because of dense jointing in the host rocks, so an in-situ fossil geosite had to be established. Because in-situ geoconservation was not common practice until the 1960s, the dinosaur tracks were initially conserved only as casts. Since the 1960s, the geosite has undergone regular protection measures, including impregnation, cement slurry injections, a drainage system and construction of a glass roof. In 1976, the quarry was granted the status of an open-air museum, which currently offers regularly updated panels, life-sized dinosaur models, guided tours, events, exhibitions and an anchor point in a hiking and cycling trail network. The conservation of the dinosaur track layers and the continuous improvement of touristic and educational programs have only been possible through decades of collaboration between the UNESCO Global Geopark TERRA.vita and its partners such as Osnabrück County, the City of Bad Essen, the Natural History Museum “Museum am Schölerberg” in Osnabrück, the Experiential Pedagogical Country Hostel Barkhausen and local associations.

BackgroundFew studies have assessed trajectories of alcohol use in the general population, and even fewer studies have assessed the impact of brief intervention on the trajectories. Especially for low-risk drinkers, it is unclear what trajectories occur, whether they benefit from intervention, and if so, when and how long. The aims were first, to identify alcohol use trajectories among at-risk and among low-risk drinkers, second, to explore potential effects of brief alcohol intervention and, third, to identify predictors of trajectories.MethodsAdults aged 18-64 years were screened for alcohol use at a municipal registration office. Those with alcohol use in the past 12 months (N = 1646; participation rate: 67%) were randomized to assessment plus computer-generated individualized feedback letters or assessment only. Outcome was drinks/week assessed at months 3, 6, 12, and 36. Alcohol risk group (at-risk/low-risk) was determined using the Alcohol Use Disorders Identification Test–Consumption. Latent class growth models were estimated to identify alcohol use trajectories among each alcohol risk group. Sex, age, school education, employment status, self-reported health, and smoking status were tested as predictors.ResultsFor at-risk drinkers, a light-stable class (46%), a medium-stable class (46%), and a high-decreasing class (8%) emerged. The light-stable class tended to benefit from intervention after 3 years (Incidence Rate Ratio, IRR=1.96; 95% Confidence Interval, CI: 1.14–3.37). Male sex, higher age, more years of school, and current smoking decreased the probability of belonging to the light-stable class (p-values

Background: Optimal lesion formation during catheter-based radiofrequency current (RFC) ablation depends on electro-mechanical tip-tissue coupling measurable via contact force (CF) and local impedance (LI) monitoring. We aimed to investigate CF and LI dynamics in patients with previous atrial fibrillation (AF) ablation who frequently present with heterogenous arrhythmia substrate.Methods: Data from consecutive patients presenting for repeat AF or atrial tachycardia ablation using a novel open-irrigated single-tip ablation catheter were studied. RFC applications were investigated regarding CF, LI and the maximum LI drop (∆LI) for evaluation of ablation efficacy. ∆LI > 20 Ω was defined as a successful RFC application.Results: A total of 730 RFC applications in 20 patients were analyzed. Baseline CF was not associated with baseline LI (R = 0.06, p = 0.17). A mean CF < 8 g during ablation resulted in lower ∆LI ( 20 Ω (area under the receiver operating characteristic curve (AUC) 0.75) better compared to baseline LI (AUC 0.72), mean CF (AUC 0.60), force-time integral (AUC 0.59) and local bipolar voltage (0.55).Conclusion: Combination of CF and LI may aid monitoring real-time catheter-tissue electro-mechanical coupling and lesion formation within heterogenous atrial arrhythmia substrate in patients with repeat AF or atrial tachycardia ablation.

Abstract Objectives To estimate mortality on grounds of the severity of alcohol dependence which has been assessed by two approaches: the frequency of alcohol dependence symptoms (FADS) and the number of alcohol dependence criteria (NADC). Methods A random sample of adult community residents in northern Germany at age 18 to 64 had been interviewed in 1996. Among 4075 study participants at baseline, for 4028 vital status was ascertained 20 years later. The FADS was assessed by the Severity of Alcohol Dependence Scale among the 780 study participants who had one or more symptoms of alcohol dependence or abuse and vital status information. The NADC was estimated by the Munich Composite International Diagnostic Interview among 4028 study participants with vital status information. Cox proportional hazard models were used. Results The age‐adjusted hazard ratio for the FADS (value range: 0–79) was 1.02 (95% confidence interval, CI: 1.016–1.028), for the NADC (value range: 0–7) it was 1.25 (CI: 1.19–1.32). Conclusions The FADS and NADC predicted time to death in a dose‐dependent manner in this adult general population sample.

Grain collisions in aeolian events, e.g., due to saltation, result in atmospheric aerosols. They may regularly be electrically charged, but individual charge balances in collisions including small grains are not easily obtained on the ground. We therefore approach this problem in terms of microgravity, which allows for the observation of collisions and the determination of small charges. In a drop tower experiment, ∼1 mm dust aggregates are traced before and after a collision within the electric field of a plate capacitor. The sum of the electric charge of two particles (total charge) before and after the collision often strongly deviates from charge conservation. Due to the average low collision velocities of 0.2 m/s, there is no large scale fragmentation. However, we do observe small charged particles emerging from collisions. The smallest of these particles are as small as the current resolution limit of the optical system, i.e., they are at least as small as tens of µm. In the given setting, these small fragments may carry 1 nC/m2–1 µC/m2 which is between 1% and ten times the surface charge density of the large aggregates. These first experiments indicate that collisions of charged aggregates regularly shed charged grains into the atmosphere, likely down to the suspendable aerosol size.

Our understanding of the long-term consequences of chronic ionising radiation for living organisms remains scarce. Modern molecular biology techniques are helpful tools for researching pollutant effects on biota. To reveal the molecular phenotype of plants growing under chronic radiation exposure, we sampled Vicia cracca L. plants in the Chernobyl exclusion zone and areas with normal radiation backgrounds. We performed a detailed analysis of soil and gene expression patterns and conducted coordinated multi-omics analyses of plant samples, including transcriptomics, proteomics, and metabolomics. Plants growing under chronic radiation exposure showed complex and multidirectional biological effects, including significant alterations in the metabolism and gene expression patterns of irradiated plants. We revealed profound changes in carbon metabolism, nitrogen reallocation, and photosynthesis. These plants showed signs of DNA damage, redox imbalance, and stress responses. The upregulation of histones, chaperones, peroxidases, and secondary metabolism was noted.

Abstract Background Atrial fibrillation (AF) is characterized by the repetitive regeneration of unstable rotational events, the pivot of which are known as phase singularities (PSs). The spatial concentration and distribution of PSs have not been systematically investigated using quantitative statistical approaches. Objectives We utilized a geospatial statistical approach to determine the presence of local spatial concentration and global clustering of PSs in biatrial human AF recordings. Methods 64‐electrode conventional basket (~5 min, n = 18 patients, persistent AF) recordings were studied. Phase maps were produced using a Hilbert‐transform based approach. PSs were characterized spatially using the following approaches: (i) local “hotspots” of high phase singularity (PS) concentration using Getis‐Ord Gi* (Z ≥ 1.96, P ≤ .05) and (ii) global spatial clustering using Moran's I (inverse distance matrix). Results Episodes of AF were analyzed from basket catheter recordings (H: 41 epochs, 120 000 s, n = 18 patients). The Getis‐Ord Gi* statistic showed local PS hotspots in 12/41 basket recordings. As a metric of spatial clustering, Moran's I showed an overall mean of 0.033 (95% CI: 0.0003‐0.065), consistent with the notion of complete spatial randomness. Conclusion Using a systematic, quantitative geospatial statistical approach, evidence for the existence of spatial concentrations (“hotspots”) of PSs were detectable in human AF, along with evidence of spatial clustering. Geospatial statistical approaches offer a new approach to map and ablate PS clusters using substrate‐based approaches.

Abstract Background The Patient Health Questionnaire-8 (PHQ-8) is a screening questionnaire of depressive symptoms. However, it is unknown whether it is equivalent across time and between groups of individuals. The aim of our paper was to test whether the PHQ-8 has the same meaning in two groups of individuals over time. Methods Primary care patients were proactively recruited from three German cities. PHQ-8 data from a baseline assessment (n = 588), two assessments during the intervention (n = 246/225), and a six (n = 437) and 12 months (n = 447) follow-up assessment were first used to examine the factor structure of the PHQ-8 by confirmatory factor analysis (CFA). The best fitting factor solution was then used to test longitudinal invariance across time and between intervention and control group by Multiple Group CFA. Results A two-factor structure consistently showed the best model fit. Only configural longitudinal invariance was evidenced when the baseline assessment was included in the analysis. Without the baseline assessment, strict longitudinal invariance was shown across the intervention and the follow-up assessments. Scalar invariance was established between the intervention and control group for the baseline assessment and strict invariance between groups and across the 6- and 12-month follow-up assessments. Conclusions The lack of longitudinal invariance might be attributed to various differences between the baseline assessments and all following assessments, e.g., assessment mode (iPad vs telephone), potential changes in symptom perception, and setting. Trial registration DRKS0001163 5, date of trial registration: 20.01.2017; DRKS00011637 , date of trial registration: 25.01.2017.

BackgroundThe alcohol-attributable burden of disease is high among socially disadvantaged individuals. Interventional efforts intending to have a public health impact should also address the reduction of social inequalities due to alcohol. ObjectiveThe aim was to test the moderating role of educational background on the efficacy of a computer-based brief intervention addressing the full spectrum of alcohol use. MethodsWe recruited 1646 adults from the general population aged 18 to 64 years (920 women, 55.9%; mean age 31 years; 574 with less than 12 years of school education, 34.9%) who reported alcohol use in the past year. The participants were randomly assigned a brief alcohol intervention or to assessment only (participation rate, 66.9%, 1646/2463 eligible persons). Recruitment took place in a municipal registry office in one German city. All participants filled out a self-administered, tablet-based survey during the recruitment process and were assessed 3, 6, and 12 months later by study assistants via computer-assisted telephone interviews. The intervention consisted of 3 computer-generated and individualized feedback letters that were sent via mail at baseline, month 3, and month 6. The intervention was based on the transtheoretical model of behavior change and expert system software that generated the feedback letters automatically according to previously defined decision rules. The outcome was self-reported change in number of alcoholic drinks per week over 12 months. The moderator was school education according to highest general educational degree (less than 12 years of education vs 12 years or more). Covariates were sex, age, employment, smoking, and alcohol-related risk level. ResultsLatent growth modeling revealed that the intervention effect after 12 months was moderated by educational background (incidence rate ratio 1.38, 95% CI 1.08-1.76). Individuals with less than 12 years of school education increased their weekly alcohol use to a lesser extent when they received the intervention compared to assessment only (incidence rate ratio 1.30, 95% CI 1.05-1.62; Bayes factor 3.82). No difference was found between groups (incidence rate ratio 0.95, 95% CI 0.84-1.07; Bayes factor 0.30) among those with 12 or more years of school education. ConclusionsThe efficacy of an individualized brief alcohol intervention was moderated by the participants’ educational background. Alcohol users with less than 12 years of school education benefited, whereas those with 12 or more years did not. People with lower levels of education might be more receptive to the behavior change mechanisms used by brief alcohol interventions. The intervention approach may support the reduction of health inequalities in the population at large if individuals with low or medium education can be reached. Trial RegistrationGerman Clinical Trials Register DRKS00014274; https://www.drks.de/DRKS00014274

Abstract Background The sedentary polychaete Sabellaria alveolata, the sandcastle or honeycomb worm, possesses four different kinds of appendages besides the parapodia: opercular papillae, tentacular filaments, palps, and branchiae. It exhibits a highly specialized anterior end, the operculum, formed by the prostomium, peristomium, and two anterior segments. The operculum comprises opercular papillae, tentacular filaments, and palps. Paired branchiae are present from the second thoracic chaetiger onwards on the posteriorly following segments except for the last ones. Ultrastructural data on these appendages are either scanty, incomplete, or even lacking in Sabellariidae. In order to analyze their functional morphology, to bridge the data gap, and providing data for future phylogenetic and evolutionary analyses, we investigated the appendages of S. alveolata by applying light microscopy, confocal laser scanning microscopy, scanning, and transmission electron microscopy. Results In S. alveolata the entire body is covered by a thin cuticle characterized by the absence of layers of parallel collagen fibers with no differentiation between the various body regions including the branchiae. The opercular papillae bear numerous tufts of receptor cells and lack motile cilia. The tentacular filaments show a distinctive pattern of motile cilia. Their most conspicuous morphological feature is a cell-free cartilaginous endoskeletal structure enclosed by ECM. Besides musculature the filaments include a single coelomic cavity but blood vessels are absent. The palps are ciliated and possess two coelomic cavities and a single blind-ending internal blood vessel. Besides external ciliation and receptor cells, the coelomate branchiae are highly vascularized and equipped with numerous blood spaces extending deep between the epidermal cells resulting in low diffusion distances. Conclusions All appendages, including the branchiae, bear receptor cells and, as such, are sensory. The opercular papillae resemble typical parapodial cirri. In contrast, the tentacular filaments have a triple function: sensing, collecting and transporting particles. A similarity to branchiae can be excluded. The palps are typical grooved palps. A revised classification of polychaete branchiae is suggested; thereby, the branchiae of S. alveolata belong to the most common type comprising coelom, musculature, and blood vessels. The results indicate that diffusion distances between blood and environment have been underestimated in many cases.

Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007.

The estimation of the direction-of-arrival in a coherent multi-channel radar system requires the distribution of the high-frequency local oscillator signal to all hardware channels. Various system concepts with distribution network or feedthrough topologies are established. While distribution networks are bulky and costly, the time delays in systems with a feedthrough topology cause systematic errors in the range evaluation. In this work, a system concept based on an injection-locked feedthrough and the related radar system analysis is presented. The disadvantage of time delays in common feedthrough architectures can be eliminated by a hardware correction using the phase shifting capabilities of the injection-locked oscillator. In addition, two software correction algorithms are presented and analyzed. The performance of the realized system is shown by radar measurements and direction-of-arrival estimations. It is proven that the phase noise of different injection-locked oscillators is fully correlated within the radar system which results in the same detection performance as in state-of-the-art radar systems using a signal distribution network. Thus, the injection-locked feedthrough imaging radar topology is a suitable concept of realizing flexible radar frontends without bulky distribution networks.

Limbachia et al conduct a fMRI study in which participants are shown stressful stimuli that is either controllable or not. They show that the ability to control a stressor results in reduced activity in key areas of the brain that coordinate responses to a perceived threat.

IntroductionCatheter ablation of ventricular arrhythmias emerging from the ventricular outflow tracts and adjacent structures is very effective and considered almost curative in patients without structural heart disease (SHD). Outcomes of patients with SHD undergoing ablation of outflow tract arrhythmias are not known.MethodsConsecutive patients (2019–2021) undergoing catheter ablation of ventricular arrhythmias in a single high-volume center were retrospectively analyzed. Patients with ablation of outflow tract arrhythmias were identified and divided in individuals with and without SHD. Procedural parameters and acute outcome were compared.ResultsWe identified 215 patients with outflow tract arrhythmias (35.3% female, mean age 58.3 ± 16.0 years). Of those, 93 (43.3%) had SHD. Patients with SHD and outflow tract arrhythmias were older (65.0 ± 12.8 vs. 53.3 ± 16.3 years; p < 0.001), more often male (82.8 vs. 50.0%; p < 0.001) and had more comorbidities than patients without SHD (arterial hypertension: 62.4 vs. 34.4%, p < 0.001; diabetes: 22.6 vs. 8.2%, p = 0.005; chronic lung disease: 20.4 vs. 7.4%, p = 0.007). Outflow tract arrhythmias in patients with SHD had their origin more often in the left ventricle (68.8 vs. 53.3%, p = 0.025). The acute success rate was similar in both patient groups (93.4 vs. 94.2%, p = 0.781). Patients with SHD were discharged later {median length of hospital stay with SHD 5 [6 (interquartile range)] days, without SHD 2 [4] days, p < 0.001}. Periprocedural complications were numerically more frequent in patients with SHD [with SHD 12 (12.9%), without SHD 8 (6.6%), p = 0.154].ConclusionOutflow tract arrhythmia ablation has a high success rate irrespective of the presence of SHD. Longer hospital stay and potentially a higher risk of periprocedural complications should be considered when discussing this treatment option with patients.

Background: Recent clinical trials demonstrate the feasibility of neoadjuvant immuno(chemo)therapy and report high rates of pathological remission, a surrogate marker for overall survival. Patients and methods: This is a retrospective multicentre real-world analysis of patients with locally resectable NSCLC, including oligometastatic disease, who received neoadjuvant immuno(chemo)therapy and resection. Consolidating immunotherapy was applied following multidisciplinary board recommendation. Primary endpoint was the rate of complete pathological response (pCR, no residual vital tumour cells) or major pathological response (MPR, ⩽ 10% residual vital tumour cells). Secondary endpoints included the radiological response and survival. Results: Seven centres contributed 59 patients (56% stage IIB–IIIC, 44% in stage IVA–IVB with up to four oligometastatic sites). MPR was found in 68% including 53% with pCR. There were no radiological progressions. Median follow-up was 24.3 months. At 12 and 24 months, progression-free survival was 82.6% and 68.1%, and overall survival was 89.5% and 87.2%, respectively. Conclusion: To our knowledge, this study encompassed the largest NSCLC real-world cohort treated with neoadjuvant immuno(chemo)therapy to date. In routine clinical practice, resection after neoadjuvant immuno(chemo)therapy is feasible in patients with locally resectable NSCLC, including oligometastatic disease. In line with clinical trials, we found MPR in more than two-thirds of patients. Early data show encouraging survival.

Abstract Background Catheter ablation of non-reentrant, commonly termed “idiopathic” ventricular arrhythmias (VA) is highly effective in patients without structural heart disease (SHD). Meanwhile, the outcome of catheter ablation of these arrhythmias in patients with SHD remains unclear. This study sought to characterize the outcome of patients with and without SHD undergoing catheter ablation of non-reentrant VA. Methods In this single-centre study the acute and long-term outcome of 266 consecutive patients undergoing catheter ablation of non-reentrant VA was investigated. In 41.0% of patients a SHD was present (n = 109, 80.7% male, age 59.1 ± 14.7 years), 59.0% had no SHD (n = 157; 44.0% male, age 49.9 ± 16.5 years). Results Acute procedural success (absence of spontaneous or provoked VA at the end of procedure and within 48 h after the procedure) was achieved in 89.9% of patients with SHD vs. 94.3% without SHD (p = 0.238). During a mean follow-up of 34.7 ± 15.1 months a repeat catheter ablation was performed in 19.6% of patients with SHD vs. 13.0% without SHD (p = 0.179). Patients with dilated cardiomyopathy (DCM) were the most likely to require a repeat ablation procedure (32.0% of patients with DCM vs. 13.0% without SHD; p = 0.022). Periprocedural complications occurred in 5.5% of patients with SHD vs. 5.7% without SHD (p > 0.999). All complications were managed without sequelae. Conclusions The outcome of catheter ablation of non-reentrant VA in patients with SHD appears good and is comparable to patients without SHD. A slightly higher rate of repeat ablations was observed in patients with DCM.

Abstract Background Acute respiratory distress syndrome continues to drive significant morbidity and mortality after severe trauma. The incidence of trauma-induced, moderate-to-severe hypoxaemia, according to the Berlin definition, could be as high as 45%. Its pathophysiology includes the release of damage-associated molecular patterns (DAMPs), which propagate tissue injuries by triggering neutrophil extracellular traps (NETs). NETs include a DNA backbone coated with cytoplasmic proteins, which drive pulmonary cytotoxic effects. The structure of NETs and many DAMPs includes double-stranded DNA, which prevents their neutralization by plasma. Dornase alfa is a US Food and Drug Administration-approved recombinant DNase, which cleaves extracellular DNA and may therefore break up the backbone of NETs and DAMPs. Aerosolized dornase alfa was shown to reduce trauma-induced lung injury in experimental models and to improve arterial oxygenation in ventilated patients. Methods TRAUMADORNASE will be an institution-led, multicentre, double-blinded, placebo-controlled randomized trial in ventilated trauma patients. The primary trial objective is to demonstrate a reduction in the incidence of moderate-to-severe hypoxaemia in severe trauma patients during the first 7 days from 45% to 30% by providing aerosolized dornase alfa as compared to placebo. The secondary objectives are to demonstrate an improvement in lung function and a reduction in morbidity and mortality. Randomization of 250 patients per treatment arm will be carried out through a secure, web-based system. Statistical analyses will include a descriptive step and an inferential step using fully Bayesian techniques. The study was approved by both the Agence Nationale de la Sécurité du Médicament et des Produits de Santé (ANSM, on 5 October 2018) and a National Institutional Review Board (CPP, on 6 November 2018). Participant recruitment began in March 2019. Results will be published in international peer-reviewed medical journals. Discussion If early administration of inhaled dornase alfa actually reduces the incidence of moderate-to-severe hypoxaemia in patients with severe trauma, this new therapeutic strategy may be easily implemented in many clinical trauma care settings. This treatment may facilitate ventilator weaning, reduce the burden of trauma-induced lung inflammation and facilitate recovery and rehabilitation in severe trauma patients. Trial registration ClinicalTrials.gov, NCT03368092 . Registered on 11 December 2017.

Purpose: Patients with large, high-grade soft tissue sarcomas are commonly treated with aggressive limb preservation regimens. This study aimed to assess cancer control outcomes of patients treated with neoadjuvant chemoradiation (CRT) compared with radiation therapy (RT) alone. Methods: We reviewed records of patients with high-grade extremity or trunk soft tissue sarcomas ≥5 cm who were treated with neoadjuvant radiation with or without chemotherapy. Patient and disease characteristics were compared using t test and χ2 tests. Standardized mortality ratio weighted method was used to compare overall survival (OS), local control, and disease-free (DFS) survival. Acute radiation and surgical toxicity were reported. Results: In the study, 64 patients (34 CRT and 30 RT) treated between 1997 and 2015 were analyzed. In the RT group compared with the CRT group, the patient population was older, with a median age of 65 versus 50 years (P < .001), and more likely to have cardiovascular disease (CVD; 30% vs 0%, P < .001). At a median follow-up of 41 months, after adjusting for propensity score of receiving RT, the 3-year LC was 87.3% versus 86.1%, DFS was 58.5% versus 56.6%, and OS was 75.6% versus 69.0% for the CRT and RT groups, respectively (P > .05). Acute dermatitis occurred in 18% versus 3% and surgical complications occurred in 32% versus 17% of CRT and RT patients, respectively. Conclusions: In this study, patients receiving RT alone were more likely to be older and have comorbid cardiovascular disease. When controlling for baseline differences, neoadjuvant CRT and RT provided similar rates of LC, DFS, and OS.

Abstract Purpose of Review Atrial fibrillation (AF), the most common sustained arrhythmia, is associated with high rates of morbidity and mortality. Maintenance of stable sinus rhythm (SR) is the intended treatment target in symptomatic patients, and catheter ablation aimed at isolating the pulmonary veins provides the most effective treatment option, supported by encouraging clinical outcome data. A variety of energy sources and devices have been developed and evaluated. In this review, we summarize the current state of the art of catheter ablation of AF and describe future perspectives. Recent Findings Catheter ablation is a well-established treatment option for patients with symptomatic AF and is more successful at maintaining SR than antiarrhythmic drugs. Antral pulmonary vein isolation (PVI) as a stand-alone ablation strategy results in beneficial clinical outcomes and is therefore recommended as first-line strategy for both paroxysmal and persistent AF. While radiofrequency-based PVI in conjunction with a three-dimensional mapping system was for many years considered to be the “gold standard”, the cryoballoon has emerged as the most commonly used alternative AF ablation tool, especially in patients with paroxysmal AF. Patients with persistent or long-standing persistent AF and with arrhythmia recurrence after previous PVI may benefit from additional ablation strategies, such as substrate modification of various forms or left atrial appendage isolation. New technologies and techniques, such as identification of the AF sources and magnetic resonance imaging-guided substrate modification, are on the way to further improve the success rates of catheter ablation for selected patients and might help to further reduce arrhythmia recurrence. Conclusions Pulmonary vein isolation is the treatment of choice for symptomatic patients with paroxysmal and persistent drug-refractory AF. The reconnection of previously isolated pulmonary veins remains the major cause of AF recurrence. Novel ablation tools, such as balloon technologies or alternative energy sources, might help to overcome this limitation. Patients with non-paroxysmal AF and with AF recurrence might benefit from alternative ablation strategies. However, further studies are warranted to further improve our knowledge of the underlying mechanisms of AF and to obtain long-term clinical outcomes on new ablation techniques.

Summary: Background: Cardiac autonomic dysfunction after myocardial infarction identifies patients at high risk despite only moderately reduced left ventricular ejection fraction. We aimed to show that telemedical monitoring with implantable cardiac monitors in these patients can improve early detection of subclinical but prognostically relevant arrhythmic events. Methods: We did a prospective investigator-initiated, randomised, multicentre, open-label, diagnostic trial at 33 centres in Germany and Austria. Survivors of acute myocardial infarction with left ventricular ejection fraction of 36–50% had biosignal analysis for assessment of cardiac autonomic function. Patients with abnormal periodic repolarisation dynamics (≥5·75 deg2) or abnormal deceleration capacity (≤2·5 ms) were randomly assigned (1:1) to telemedical monitoring with implantable cardiac monitors or conventional follow-up. Primary endpoint was time to detection of serious arrhythmic events defined by atrial fibrillation 6 min or longer, atrioventricular block class IIb or higher and fast non-sustained (>187 beats per min; ≥40 beats) or sustained ventricular tachycardia or fibrillation. This study is registered with ClinicalTrials.gov, NCT02594488. Findings: Between May 12, 2016, and July 20, 2020, 1305 individuals were screened and 400 patients at high risk were randomly assigned (median age 64 years [IQR 57–73]); left ventricular ejection fraction 45% [40–48]) to telemedical monitoring with implantable cardiac monitors (implantable cardiac monitor group; n=201) or conventional follow-up (control group; n=199). During median follow-up of 21 months, serious arrhythmic events were detected in 60 (30%) patients of the implantable cardiac monitor group and 12 (6%) patients of the control group (hazard ratio 6·33 [IQR 3·40–11·78]; p

Background Evidence suggests that people who abstain from alcohol have a higher mortality rate than those who drink low to moderate amounts. However, little is known about factors that might be causal for this finding. The objective was to analyze former alcohol or drug use disorders, risky drinking, tobacco smoking, and fair to poor health among persons who reported abstinence from alcohol drinking in the last 12 months before baseline in relation to total, cardiovascular, and cancer mortality 20 years later. Methods and findings A sample of residents aged 18 to 64 years had been drawn at random among the general population in northern Germany and a standardized interview conducted in the years 1996 to 1997. The baseline assessment included 4,093 persons (70.2% of those who had been eligible). Vital status and death certificate data were retrieved in the years 2017 and 2018. We found that among the alcohol-abstinent study participants at baseline (447), there were 405 (90.60%) former alcohol consumers. Of the abstainers, 322 (72.04%) had met one or more criteria for former alcohol or drug dependence or abuse, alcohol risky drinking, or had tried to cut down or to stop drinking, were daily smokers, or self-rated their health as fair to poor. Among the abstainers with one or more of these risk factors, 114 (35.40%) had an alcohol use disorder or risky alcohol consumption in their history. Another 161 (50.00%) did not have such an alcohol-related risk but were daily smokers. The 322 alcohol-abstinent study participants with one or more of the risk factors had a shorter time to death than those with low to moderate alcohol consumption. The Cox proportional hazard ratio (HR) was 2.44 (95% confidence interval (CI), 1.68 to 3.56) for persons who had one or more criteria for an alcohol or drug use disorder fulfilled in their history and after adjustment for age and sex. The 125 alcohol-abstinent persons without these risk factors (27.96% of the abstainers) did not show a statistically significant difference from low to moderate alcohol consumers in total, cardiovascular, and cancer mortality. Those who had stayed alcohol abstinent throughout their life before (42; 9.40% of the alcohol-abstinent study participants at baseline) had an HR 1.64 (CI 0.72 to 3.77) compared to low to moderate alcohol consumers after adjustment for age, sex, and tobacco smoking. Main limitations of this study include its reliance on self-reported data at baseline and the fact that only tobacco smoking was analyzed as a risky behavior alongside alcohol consumption. Conclusions The majority of the alcohol abstainers at baseline were former alcohol consumers and had risk factors that increased the likelihood of early death. Former alcohol use disorders, risky alcohol drinking, ever having smoked tobacco daily, and fair to poor health were associated with early death among alcohol abstainers. Those without an obvious history of these risk factors had a life expectancy similar to that of low to moderate alcohol consumers. The findings speak against recommendations to drink alcohol for health reasons. In this cohort study conducted over 20 years, Ulrich John and colleagues examine the relationship between alcohol abstinence and mortality in a German adult population. Author summary Why was this study done? According to evidence, alcohol abstinence seems to be associated with a lower life expectancy than low to moderate alcohol consumption. Individuals who abstain from alcohol might include those who have risk factors that can be reasons for the shorter life expectancy compared to low to moderate alcohol consumers. What did the researchers do and find? A random adult general population sample had been drawn and the study participants been inquired about their consumption of or abstinence from alcohol in a first contact. Twenty years later, proportions of deceased and time to death were determined and compared between former alcohol abstainers and low to moderate alcohol consumers among the 4,028 study participants. The findings show that 91% of the alcohol abstainers at first contact had consumed alcohol in life before and 72% had a history of one or more criteria of a former alcohol or drug use disorder, former risky alcohol consumption, efforts to cut down or to stop drinking, daily tobacco smoking, or fair to poor health. In terms of mortality rate, no statistically significant difference was apparent between alcohol abstinent persons without these risk factors and who had self-rated their health as good to excellent and persons who consumed low to moderate amounts of alcohol. What do these findings mean? Former alcohol use disorders, risky consumption, efforts to cut down on drinking, ever daily tobacco smoking, and fair to poor health may predict early death among alcohol abstainers. Healthy alcohol abstainers who have no alcohol- or tobacco-related risk factors may not have a higher mortality than low to moderate alcohol consumers. The findings speak against recommendations to drink alcohol for health reasons.

Antigen-specific tissue-resident memory T cells (Trms) and neutralizing IgA antibodies provide the most effective protection of the lungs from viral infections. To induce those essential components of lung immunity against SARS-CoV-2, we tested various immunization protocols involving intranasal delivery of a novel Modified Vaccinia virus Ankara (MVA)-SARS-2-spike vaccine candidate. We show that a single intranasal MVA-SARS-CoV-2-S application in mice strongly induced pulmonary spike-specific CD8+ T cells, albeit restricted production of neutralizing antibodies. In prime-boost protocols, intranasal booster vaccine delivery proved to be crucial for a massive expansion of systemic and lung tissue-resident spike-specific CD8+ T cells and the development of Th1 - but not Th2 - CD4+ T cells. Likewise, very high titers of IgG and IgA anti-spike antibodies were present in serum and broncho-alveolar lavages that possessed high virus neutralization capacities to all current SARS-CoV-2 variants of concern. Importantly, the MVA-SARS-2-spike vaccine applied in intramuscular priming and intranasal boosting treatment regimen completely protected hamsters from developing SARS-CoV-2 lung infection and pathology. Together, these results identify intramuscular priming followed by respiratory tract boosting with MVA-SARS-2-S as a promising approach for the induction of local, respiratory as well as systemic immune responses suited to protect from SARS-CoV-2 infections.

How are spaces constituted through social action, and how do they constitute social action? We address these questions by studying how protesters appropriate spaces by occupying streets and public buildings and by spreading specific atmospheres. We apply Alfred SCHÜTZ's phenomenological take on the constitution of multiple realities in terms of "province of meaning" as a heuristic device to capture the diversity of protest atmospheres along with their spatial, affective, and epistemic dimensions—those embodied and situated as well as virtual. This perspective allows us to describe empirical examples of protest situations in South Africa and Senegal where "the streets" and the media meet. Our research material spans documents, tweets, video material collected online, and ethnographic interviews. In this article, we look at how embodied practices reproduce and manifest particular "provinces of meaning" and "protest atmospheres," and how these embodied practices are complemented by social media practices. Our proposed approach not only provides an example of how a social space is created and refigured through social protest, but also allows a further understanding of the situational emergence of protests as collective action that creates "we-experiences." The phenomenological perspective goes beyond the widespread mind/body dualism that underlies so many interpretations of social movement culture.

Introduction Spinal cord injury (SCI) is a devastating condition with immediate impact on the individual’s health and quality of life. Major functional recovery reaches a plateau 3–4 months after injury despite intensive rehabilitative training. To enhance training efficacy and improve long-term outcomes, the combination of rehabilitation with electrical modulation of the spinal cord and brain has recently aroused scientific interest with encouraging results. The mesencephalic locomotor region (MLR), an evolutionarily conserved brainstem locomotor command and control centre, is considered a promising target for deep brain stimulation (DBS) in patients with SCI. Experiments showed that MLR-DBS can induce locomotion in rats with spinal white matter destructions of >85%.Methods and analysis In this prospective one-armed multi-centre study, we investigate the safety, feasibility, and therapeutic efficacy of MLR-DBS to enable and enhance locomotor training in severely affected, subchronic and chronic American Spinal Injury Association Impairment Scale C patients in order to improve functional recovery. Patients undergo an intensive training programme with MLR-DBS while being regularly followed up until 6 months post-implantation. The acquired data of each timepoint are compared with baseline while the primary endpoint is performance in the 6-minute walking test. The clinical trial protocol was written in accordance with the Standard Protocol Items: Recommendations for Interventional Trials checklist.Ethics and dissemination This first in-man study investigates the therapeutic potential of MLR-DBS in SCI patients. One patient has already been implanted with electrodes and underwent MLR stimulation during locomotion. Based on the preliminary results which promise safety and feasibility, recruitment of further patients is currently ongoing. Ethical approval has been obtained from the Ethical Committee of the Canton of Zurich (case number BASEC 2016-01104) and Swissmedic (10000316). Results will be published in peer-reviewed journals and presented at conferences.Trial registration number NCT03053791.