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Quasi-universal behavior of the threshold mass in unequal-mass, spinning binary neutron star mergers
(2021)
The lifetime of the remnant produced by the merger of two neutron stars can provide a wealth of information on the equation of state of nuclear matter and on the processes leading to the electromagnetic counterpart. Hence, it is essential to determine when this lifetime is the shortest, corresponding to when the remnant has a mass equal to the threshold mass, Mth, to prompt collapse to a black hole. We report on the results of more than 360 simulations of merging neutron-star binaries covering 40 different configurations differing in mass ratio and spin of the primary. Using this data, we have derived a quasi-universal relation for Mth and expressed its dependence on the mass ratio and spin of the binary. The new expression recovers the results of Koeppel et al. for equal-mass, irrotational binaries and reveals that Mth can increase (decrease) by 5% (10%) for binaries that have spins aligned (antialigned) with the orbital angular momentum and provides evidence for a nonmonotonic dependence of Mth on the mass asymmetry in the system. Finally, we extend to unequal masses and spinning binaries the lower limits that can be set on the stellar radii once a neutron star binary is detected, illustrating how the merger of an unequal-mass, rapidly spinning binary can significantly constrain the allowed values of the stellar radii.
Neutron-induced cross sections of short-lived nuclei are highly relevant in many domains such as fundamental nuclear physics, astrophysics and applications in nuclear technology. In particular, these cross sections are essential for understanding the synthesis of elements via the s- and r stellar processes. However, the measurement of such cross sections with current techniques is very difficult or even impossible, because of the difficulties to produce and handle the necessary amounts of radioactive nuclei. Reaching the nuclei of interest is only possible by inverting the reaction kinematics with radioactive beams.
In this contribution we present a project for indirectly determining neutron cross sections via the surrogate-reaction method. This project is based on the measurement of transfer- or inelastic-scattering-induced decay probabilities in inverse kinematics at storage rings. The measured probabilities are then used to tune nuclear-reaction models that will provide much more accurate predictions of the desired neutron cross sections. We also discuss a very ambitious, long-term project to directly measure neutron cross sections in inverse kinematics. It consists in the combination of a radioactive beam facility, an ion storage ring and a spallation neutron source.
The SU(3) pure gauge theory exhibits a first-order thermal deconfinement transition due to spontaneous breaking of its global Z3 center symmetry. When heavy dynamical quarks are added, this symmetry is broken explicitly and the transition weakens with decreasing quark mass until it disappears at a critical point. We compute the critical hopping parameter and the associated pion mass for lattice QCD with Nf=2 degenerate standard Wilson fermions on Nτ∈{6,8,10} lattices, corresponding to lattice spacings a=0.12 fm, a=0.09 fm, a=0.07 fm, respectively. Significant cutoff effects are observed, with the first-order region growing as the lattice gets finer. While current lattices are still too coarse for a continuum extrapolation, we estimate mcπ≈4 GeV with a remaining systematic error of ∼20%. Our results allow us to assess the accuracy of the leading-order and next-to-leading-order hopping expanded fermion determinant used in the literature for various purposes. We also provide a detailed investigation of the statistics required for this type of calculation, which is useful for similar investigations of the chiral transition.
Purpose of Review: To review the latest developments and the current role of the cardiac magnetic resonance (CMR) in pericardial diseases and their complications.
Recent Findings: Cardiac Magnetic Resonance (CMR) has the ability to incorporate anatomy, physiology, and “virtual histology” strategies to achieve the most accurate diagnosis for even the most demanding, pericardial diseases.
Summary: Acute, chronic, recurrent, and constrictive pericarditis as well as pericarditis related complications, pericardial masses and congenital pericardial defects are commonly encountered in clinical practice with relatively significant morbidity and mortality. Owing to the challenging diagnosis, CMR imaging is often employed in confirming the diagnosis and elucidating the underling pathophysiology. In this review we outline the common CMR techniques and their expected diagnostic outcomes.
Modeling long-term neuronal dynamics may require running long-lasting simulations. Such simulations are computationally expensive, and therefore it is advantageous to use simplified models that sufficiently reproduce the real neuronal properties. Reducing the complexity of the neuronal dendritic tree is one option. Therefore, we have developed a new reduced-morphology model of the rat CA1 pyramidal cell which retains major dendritic branch classes. To validate our model with experimental data, we used HippoUnit, a recently established standardized test suite for CA1 pyramidal cell models. The HippoUnit allowed us to systematically evaluate the somatic and dendritic properties of the model and compare them to models publicly available in the ModelDB database. Our model reproduced (1) somatic spiking properties, (2) somatic depolarization block, (3) EPSP attenuation, (4) action potential backpropagation, and (5) synaptic integration at oblique dendrites of CA1 neurons. The overall performance of the model in these tests achieved higher biological accuracy compared to other tested models. We conclude that, due to its realistic biophysics and low morphological complexity, our model captures key physiological features of CA1 pyramidal neurons and shortens computational time, respectively. Thus, the validated reduced-morphology model can be used for computationally demanding simulations as a substitute for more complex models.
Purpose: Every physician must be able to sufficiently master medical emergencies, especially in medical areas where emergencies occur frequently such as in the emergency room or emergency surgery. This contrasts with the observation that medical students and young residents often feel insufficiently prepared to handle medical emergencies. It is therefore necessary to train them in the treatment of emergency patients. The aim of this study is to analyze the influence of the assignment of manikin versus simulated patients during a training for undergraduate medical students on learning outcomes and the perceived realism.
Methods: The study had a prospective cross-over design and took place in a 3-day emergency medicine training for undergraduate medical students. Students completed three teaching units (‘chest pain’, ‘impaired consciousness’, ‘dyspnea’), either with manikin or simulated patient. Using a questionnaire after each unit, overall impression, didactics, content, the quality of practical exercises, and the learning success were evaluated. The gained competences were measured in a 6-station objective structured clinical examination (OSCE) at the end of training.
Results: 126 students participated. Students rated simulated patients as significantly more realistic than manikins regarding the possibility to carry out examination techniques and taking medical history. 54.92% of the students would prefer to train with simulated patients in the future. Regarding the gained competences for ‘chest pain’ and ‘impaired consciousness’, students who trained with a manikin scored less in the OSCE station than the simulated patients-group.
Conclusion: Simulated patients are rated more realistic than manikins and seem to be superior to manikins regarding gained competence.
Due to the continued high incidence and mortality rate worldwide, there is a need to develop new strategies for the quick, precise, and valuable recognition of presenting injury pattern in traumatized and poly-traumatized patients. Extracellular vesicles (EVs) have been shown to facilitate intercellular communication processes between cells in close proximity as well as distant cells in healthy and disease organisms. miRNAs and proteins transferred by EVs play biological roles in maintaining normal organ structure and function under physiological conditions. In pathological conditions, EVs change the miRNAs and protein cargo composition, mediating or suppressing the injury consequences. Therefore, incorporating EVs with their unique protein and miRNAs signature into the list of promising new biomarkers is a logical next step. In this review, we discuss the general characteristics and technical aspects of EVs isolation and characterization. We discuss results of recent in vitro, in vivo, and patients study describing the role of EVs in different inflammatory diseases and traumatic organ injuries. miRNAs and protein signature of EVs found in patients with acute organ injury are also debated.
Background: Surgical methods have profited from the exchange of knowledge among different specialties. Endoscopy which was introduced by gynecologists, surgeons, and internists is used now by all disciplines, and most of yesterday's laparotomies have now endoscopic alternatives. However, laparotomies are still needed, and there is no agreement among surgeons about what is the optimal abdominal incision. The Joel-Cohen incision which is used by gynecologists and obstetricians could become a valid alternative to the methods in use.
Method: The Joel-Cohen Method, which was evolved for abdominal hysterectomy is described here in detail. Only two instruments are used to open the abdomen, usually with no need for hemostasis.
Conclusion: The Joel-Cohen incision is suggested as a valid alternative for any emergency or elective surgical or urological abdominal operation. Its benefits are short operation time diminished blood loss and less need for analgesics.
Microsurgical free flap reconstruction in acute burn care offers the option of reconstructing even challenging defects in a single stage procedure. Due to altered rheological and hemodynamic conditions in severely burned patients, it bears the risk of a higher complication rate compared to microsurgical reconstruction in other patients. To avoid failure, appropriate indications for free flap reconstruction should be reviewed thoroughly. Several aspects concerning timing of the procedure, individual flap choice, selection and preparation of the recipient vessels, and perioperative measures must be considered. Respecting these specific conditions, a low complication rate, comparable to those seen in microsurgical reconstruction of other traumatic limb defects, can be observed. Hence, the free flap procedure in acute burn care is a relatively safe and reliable tool in the armamentarium of acute burn surgery. In reconstructive burn care, microsurgical tissue transfer is routinely used to treat scar contractures. Due to the more robust perioperative condition of patients, even lower rates of complication are seen in microsurgical reconstruction.
The conventional approach of looking down a microscope to perform microsurgical procedures is associated with occupational injuries, anti-ergonomic postures, and increased tremor and fatigue, all of which predispose microsurgeons to early retirement. Recently, three-dimensional (3D) visualization of real-time microscope magnification has been developed as an alternative. Despite its commercial availability, no supermicrosurgical procedures have been reported using this technology to date. Lymphovenous anastomoses (LVAs) often require suturing vessels with diameters of 0.2–0.8 mm, thus representing the ultimate microsurgical challenge. After performing the first documented LVA procedure using 3D-augmented visualization in our unit and gaining experience with this technique, we conducted an anonymized in-house survey among microsurgeons who had used this approach. The participants considered that 3D visualization for supermicrosurgery was equivalent in terms of handling, optical detail, depth resolution, and safety to conventional binocular magnification. This survey revealed that team communication, resident education, and ergonomics were superior using 3D digital hybrid visualization. Postoperative muscle fatigue, tremor, and pain were also reduced. The major drawbacks of the 3D visualization microscopic systems are the associated costs, required space, and difficulty of visualizing the lymphatic contrast used.
A positive association between brain size and intelligence is firmly established, but whether region-specific anatomical differences contribute to general intelligence remains an open question. Results from voxel-based morphometry (VBM) - one of the most widely used morphometric methods - have remained inconclusive so far. Here, we applied cross-validated machine learning-based predictive modeling to test whether out-of-sample prediction of individual intelligence scores is possible on the basis of voxel-wise gray matter volume. Features were derived from structural magnetic resonance imaging data (N = 308) using (a) a purely data-driven method (principal component analysis) and (b) a domain knowledge-based approach (atlas parcellation). When using relative gray matter (corrected for total brain size), only the atlas-based approach provided significant prediction, while absolute gray matter (uncorrected) allowed for above-chance prediction with both approaches. Importantly, in all significant predictions, the absolute error was relatively high, i.e., greater than ten IQ points, and in the atlas-based models, the predicted IQ scores varied closely around the sample mean. This renders the practical value even of statistically significant prediction results questionable. Analyses based on the gray matter of functional brain networks yielded significant predictions for the fronto-parietal network and the cerebellum. However, the mean absolute errors were not reduced in contrast to the global models, suggesting that general intelligence may be related more to global than region-specific differences in gray matter volume. More generally, our study highlights the importance of predictive statistical analysis approaches for clarifying the neurobiological bases of intelligence and provides important suggestions for future research using predictive modeling.
Background: Depression and anxiety are the most prevalent mental health difficulties in the workplace, costing the global economy $1 trillion each year. Evidence indicates that symptoms may be reduced by interventions in the workplace. This paper is the first to systematically review psychosocial interventions for depression, anxiety, and suicidal ideation and behaviours in small-to medium-size enterprises (SMEs).
Methods: A systematic search following PRISMA guidelines, registered in PROSPERO (CRD42020156275), was conducted for psychosocial interventions targeting depression, anxiety, and suicidal ideation/behaviour in SMEs. The PubMed, PsycINFO, Scopus, and two specific occupational health databases were searched, as well as four databases for grey literature, without time limit until 2nd December 2019.
Results: In total, 1283 records were identified, 70 were retained for full-text screening, and seven met the inclusion criteria: three randomised controlled trials (RCTs), three before and after designs and one non-randomised trial, comprising 5111 participants. Study quality was low to moderate according to the Quality Assessment Tool for Quantitative Studies. Five studies showed a reduction in depression and anxiety symptoms using techniques based on cognitive behavioural therapy (CBT), two reported no significant change.
Limitations: Low number and high heterogeneity of interventions and outcomes, high attrition and lack of rigorous RCTs.
Conclusions: Preliminary evidence indicates CBT-based interventions can be effective in targeting symptoms of depression and anxiety in SME employees. There may be unique challenges to implementing programmes in SMEs. Further research is needed in this important area.
The heart is the first functional organ that develops in the embryo. To become a functional organ, it undergoes several morphogenetic processes. These morphogenetic events involve different cell types, that interact with each other and respond to the surrounding extracellular matrix, as well as intrinsic and extrinsic mechanical forces, assuming different behaviors. Additionally, transcription factor networks, conserved among vertebrates, control the development.
To have a better understanding of cell behavior during development, it is necessary to find a model system that allows the investigation in vivo and at single-cell resolution. Thanks to the common evolutionary origin of the different cardiac structures, together with the conserved molecular pathways, the two-chambered zebrafish heart offers many advantages to study cell behavior during cardiac morphogenesis. Here, using the zebrafish heart as a model system, I uncovered the cell behavior behind two of the main cardiac morphogenetic events: cardiac wall maturation and cardiac valve formation.
In the first part of this study, I investigated how the cardiac wall is maintained at the molecular level. Using genetic, transcriptomic, and chimeric analyses in zebrafish, we find that Snai1b is required for myocardial wall integrity. Global loss of snai1b leads to the extrusion of CMs away from the cardiac lumen, a process we show is dependent on cardiac contractility. Examining CM junctions in snai1b mutants, we observed that N-cadherin localization was compromised, thereby likely weakening cell-cell adhesion. In addition, extruding CMs exhibit increased actomyosin contractility basally, as revealed by the specific enrichment of canonical markers of actomyosin tension - phosphorylated myosin light chain (active myosin) and the α-catenin epitope α-18. By comparing the transcriptome of wild-type and snai1b mutant hearts at the early stages of CM extrusion, we found the dysregulation of intermediate filament genes in mutants including the upregulation of desmin b. We tested the role of desmin b in myocardial wall integrity and found that CM-specific desmin b overexpression led to CM extrusion, recapitulating the snai1b mutant phenotype. Altogether, these results indicate that Snai1 is a critical regulator of intermediate filament gene expression in CMs and that it maintains the integrity of the myocardial epithelium during embryogenesis, at least in part by repressing desmin b expression.
In the second part of this study, I focused on the behavior of valve cells during cardiac development. Using the zebrafish atrioventricular valve, I focus on the valve interstitial cells which confer biomechanical strength to the cardiac valve leaflets. We find that initially AV endocardial cells migrate collectively into the cardiac jelly to form a bilayered structure; subsequently, the cells that led this migration invade the extracellular matrix (ECM) between the two EC monolayers, undergo an endothelial-to-mesenchymal transition as marked by loss of intercellular adhesion, and differentiate into VICs. These cells proliferate and are joined by a few neural crest-derived cells. VIC expansion and a switch from a pro-migratory to an elastic ECM drive valve leaflet elongation. Functional analysis of Nfatc1 reveals its requirement during VIC development. Zebrafish nfatc1 mutants form significantly fewer VICs due to reduced proliferation and impaired recruitment of endocardial and neural crest cells during the early stages of VIC development. Analysis of downstream effectors reveals that Nfatc1 promotes the expression of twist1b, a well-known regulator of epithelial-to-mesenchymal transition. This study shows for the first time that Nfatc1 regulates zebrafish VICs formation regulating valve EMT in part by regulating twist1b expression. Moreover, it proposes the zebrafish valve as an excellent model to study the cellular and molecular process that regulate VIC development and dysfunction.
In conclusion, my work: 1) identified an unsuspected role of Snai1 in maintaining the integrity of the myocardial epithelium, opening new avenues in its role in regulating cellular contractility; 2) uncovered the function of Nfatc1 in the establishment of the VIC, establishing a new model to study valve development and function.
Aortic valve (AV) and root replacement with composite graft and re-implantation of coronary arteries described first by Bentall and de Bono in 1968, is considered as a standard operation for treatment of different pathologies of the AV and aortic root. In centres where aortic valve and root repair techniques and Ross operation are well established, generally severely diseased patients remain indicated for this procedure. The aim of this study was to evaluate the early and long-term outcomes after Bentall-De Bono (BD) procedures in high-risk population with complex pathologies and multiple comorbidities.
Between 2005 and 2018, a total of 273 consecutive patients (median age 66 years; 23 % female) underwent AV and root replacement with composite-graft in so called button technique. We divided our population in the following groups: 1. acute type A aortic dissection group (ATAAD) (n = 48), 2. endocarditis group (n = 99) and 3. all other pathologies group (n = 126). The surgery has been per- formed emergent/urgent in 131 patients (49 %) and in 109 cases (40%) as a reoperation. Concomitant surgery was required in 97 patients (58%) and 167 pa- tients (61%) received a biological composite-graft.
Follow-up was completed in 96% (10 patients lost to follow-up) with a mean of 8.6 years (range 0.1-15.7 years), counting a total of 1450 patient-years. Thirty- day mortality was 17% (46 patients). The overall estimated survival in 5 and 10 years was 64% ± 3%) and 46% ±4 %). Group comparison showed a significant difference in favour of patient from the dissection group (p = 0.008). Implantation of a biological valve graft was associated with lower survival probability (p < 0.001). There was no significant difference in the freedom of reoperation rate between the groups. The same applies for freedom of postoperative endocarditis, thromboembolic events, and aortic prosthesis dysfunction. According to the uni- variate and multivariate logistic regression analysis primarily postoperative neu- rological dysfunction (OR 5.45), hypertension (OR 4.8) peripheral artery disease (OR 4.4), re-exploration for bleeding (OR 3.37) and postoperative renal replace- ment therapy (OR 3.09) were identified as leading predictors of mortality.
In conclusion, the BD operation can be performed with acceptable short- and long-term results in high-risk patients with complex aortic pathologies in a centre with well-established AV repair and Ross operation program.
Heterozygous mice that express Cre-recombinase under the dopamine transporter promoter (DAT-Cre knock in mice, or KI) are widely used for targeting midbrain dopamine neurons, under the assumption that their constitutive physiology is not affected. We report here that these mice display striking sex-dependent behavioral and molecular differences in relation to wildtypes (WT). Male and female KI mice were constitutively hyperactive, and male KI mice showed attenuated hyperlocomotor responses to amphetamine. In contrast, female KIs displayed a marked reduction in locomotion (“calming” effect) in response to the same dose of amphetamine. Furthermore, male and female DAT-Cre KI mice showed opposing differences in reinforcement learning, with females showing faster conditioning and males showing slower extinction. Other behavioral variables, including working memory and novelty preference, were not changed compared to WT. These effects were paralleled by differences in striatal DAT expression that disproportionately affected female KI mice. Our findings reveal clear limitations of the DAT-Cre line that must be considered when using this model.
The COVID-19 pandemic has called worldwide for strong governmental measures to contain its spread, associated with considerable psychological distress. This study aimed at screening a convenience sample in Germany during lockdown for perceived vulnerability to disease, knowledge about COVID-19, symptoms of depression and anxiety, and behavioral responses. In an online survey, 1358 participants completed the perceived vulnerability to disease scale (PVD), the Patient Health Questionnaire (PHQ-4), and questionnaires on knowledge about COVID-19 and self-perceived change in behaviors in response to COVID-19. Lower and upper quartiles of the PVD were used to classify individuals into low and high PVD. A confirmatory factor analysis supported three factors representing risk, preventive and adaptive behavior as behavioral responses to COVID-19 lockdown. A structural equation model showed that the score of the knowledge scale significantly predicted the self-reported increase in adaptive and preventive behavior. The score in the PVD-subscale Perceived Infectability predicted a self-reported increase in preventive behavior, whereas the Germ Aversion score predicted a self-reported increase in preventive and a decrease in risk behavior. The score in PHQ-4 predicted a higher score in the perceived infectability and germ aversion subscales, and a self-reported decrease in adaptive behavior. Low-, medium- and high-PVD groups reported distinct patterns of behavior, knowledge, and mental health symptoms. This study shows that perceived vulnerability to disease is closely linked to preventive behaviors and may enhance adaptation to COVID-19 pandemic.
Cirrhosis – the common end-stage of chronic liver disease – is associated with a cascade of events, of which intestinal bacterial overgrowth and dysbiosis are central. Bacterial toxins entering the portal or systemic circulation can directly cause hepatocyte death, while dysbiosis also affects gut barrier function and increases bacterial translocation, leading to infections, systemic inflammation and vasodilation, which contribute to acute decompensation and organ failure. Acute decompensation and its severe forms, pre-acute-on-chronic liver failure (ACLF) and ACLF, are characterised by sudden organ dysfunction (and failure) and high short-term mortality. Patients with pre-ACLF and ACLF present with high-grade systemic inflammation, usually precipitated by proven bacterial infection and/or severe alcoholic hepatitis. However, no precipitant is identified in 30% of these patients, in whom bacterial translocation from the gut microbiota is assumed to be responsible for systemic inflammation and decompensation. Different microbiota profiles may influence the rate of decompensation and thereby outcome in these patients. Thus, targeting the microbiota is a promising strategy for the prevention and treatment of acute decompensation, pre-ACLF and ACLF. Approaches include the use of antibiotics such as rifaximin, faecal microbial transplantation and enterosorbents (e.g. Yaq-001), which bind microbial factors without exerting a direct effect on bacterial growth kinetics. This review focuses on the role of microbiota in decompensation and strategies targeting microbiota to prevent acute decompensation.
Background: Nicolaides-Baraitser syndrome (NCBRS) is a rare disease caused by mutations in the SMRCA2 gene, which affects chromatin remodelling and leads to a wide range of symptoms including microcephaly, distinct facial features, recurrent seizures, and severe mental retardation. Until now, less than 100 cases have been reported. Case presentation: A 22-month old male infant with NCBRS underwent elective cleft palate surgery. The anaesthetists were challenged by the physiological condition of the patient: narrow face, very small mouth, mild tachypnea, slight sternal retractions, physical signs of partial monosomy 9p, and plagiocephalus, midface hypoplasia, V-shaped cleft palate, enhanced muscular hypotension, dysplastic kidneys (bilateral, estimated GFR: approx. 40 ml/m2), nocturnal oxygen demand, and combined apnea. In addition, little information was available about interaction of the NCBRS displayed by the patient and anaesthesia medications. Conclusions: The cleft palate was successfully closed using the bridge flap technique. Overall, we recommend to perform a trial video assisted laryngoscopy in the setting of spontaneous breathing with deep inhalative anaesthesia before administration of muscle relaxation to detect any airway difficulties while remaining spontaneoues breathing and protective reflexes.
The policy review is part of the project EQualCare: Alone but connected? Digital (in)equalities in care work and generational relationships among older people living alone, a three-year international project involving four countries: Finland, Germany, Latvia and Sweden. EQualCare interrogates inequalities by gender, cultural and socio-economic background between countries, with their different demographics and policy backgrounds. As a first step into empirical analysis, the policy review aims to set the stage for a better understanding of, and policy development on, the intersections of digitalisation with intergenerational care work and care relationships of older people living alone in Germany.
The policy review follows a critical approach, in which the problems policy documents address are not considered objective entities, but rather discursively produced knowledge that renders visible some parts of the problem which is to be solved as other possible perspectives are simultaneously excluded. Twenty publicly available documents were studied to analyse the processes in which definitions of care work and digital (in)equalities are circulated, translated and negotiated between the different levels of national government, regional governments and municipalities as well as other agencies in Germany.
The policy review consists of two parts: a background chapter providing information on the social structure of Germany, including the historical development of Germany after the Second World War, its political structure, information on the demographic situation with a focus on the 60+ age group, and the income of this age group. In addition, the background presents the structure of work and welfare, the organisation of care for old people, and the state of digitalisation in Germany. The analysis chapter includes a description of the method used as well as an overview of the documents chosen and analysed. The focus of this chapter is on the analysis of official documents that deal with the interplay of living alone in old age, care, and digitalisation.
The analysis identified four themes: firstly, ageing is framed largely as a challenge to society, whereas digitalisation is framed as a potential way to tackle social challenges, such as an ageing society. Secondly, challenges of ageing, such as need of care, are set at the individual level, requiring people to organise their care within their own families and immediate social networks, with state support following a principle of subsidiarity. Thirdly, voluntary peer support provides the basis for addressing digital support needs and strategies. Publications by lobby organisations highlight the important work done by voluntary peer support for digital training and the benefits this approach has; they also draw attention to the over-reliance on this form of unpaid support and call for an increase in professional support in ensuring all older people are supported in digital life. Fourthly, ageing as a hinderance to participation in digital life is seen as an interim challenge among younger old people already online.
In summary, the analysis shows that the connection between ageing and digitalisation remains a marginal topic in current politics. The focus on older people merely as a potential group at risk of being left behind implies a deficit perspective on ageing and a homogenising of a large and diverse age group. Lessons learnt from the pandemic should not be interpreted in a one-sided way, by merely acknowledging the increasing number of (older) people moving online, but by acknowledging intersecting inequalities that mitigate social participation.
Upon infection with SARS-CoV-2, a variety of changes happen inside the host cell. The virus hijacks host cell pathways for driving its own replication, while the host counteracts with response mechanisms. To gain a comprehensive understanding of COVID-19, caused by SARS-CoV-2 infection, and develop therapeutic strategies, it is crucial to observe these systematic changes in their entirety. In our recent studies, we followed the effects of SARS-CoV-2 infection on the human proteome, which led to the identification of several drugs that abolished viral proliferation in cells.
Purpose: To compare swept-source (SS) versus spectral-domain (SD) optical coherence tomography angiography (OCTA) for the detection of macular neovascularization (MNV).
Methods: In this prospective cohort study, 72 eyes of 54 patients with subretinal hyperreflective material (SHRM) and/or pigment epithelial detachment (PED) on OCT possibly corresponding to MNV in at least one eye were included. OCTA scans were acquired using two devices, the PLEX Elite 9000 SS-OCTA and the Spectralis SD-OCTA. Fluorescein angiography (FA) was used as reference. Two graders independently evaluated en face OCTA images using a preset slab as well as a manually modified slab, followed by a combination of en face and cross-sectional OCTA.
Results: Sensitivity (specificity) for the automated slabs was 51.7% (93.0%) for SS-OCTA versus 58.6% (95.3%) for SD-OCTA. Manual modification of segmentation increased sensitivity to 79.3% for SS-OCTA but not for SD-OCTA (58.6%). The combination of en face OCTA with cross-sectional OCTA reached highest sensitivity values (SS-OCTA: 82.8%, SD-OCTA: 86.2%), and lowest number of cases with discrepancies between SS-OCTA and SD-OCTA (4.2%). Fleiss kappa as measure of concordance between FA, SS-OCTA, and SD-OCTA was 0.56 for the automated slabs, 0.60 for the manual slabs, and 0.73 (good agreement) for the combination of en face OCTA with cross-sectional OCTA. Concordance to FA was moderate for the automated slabs and good for manual slabs and combination with cross-sectional OCTA of both devices.
Conclusion: Both devices reached comparable results regarding the detection of MNV on OCTA. Sensitivity for MNV detection and agreement between devices was best when evaluating a combination of en face and cross-sectional OCTA.
Hematopoietic stem cell transplantation (HSCT) is the therapeutic concept to cure the blood/immune system of patients suffering from malignancies, immunodeficiencies, red blood cell disorders, and inherited bone marrow failure syndromes. Yet, allogeneic HSCT bear considerable risks for the patient such as non-engraftment, or graft-versus host disease. Transplanting gene modified autologous HSCs is a promising approach not only for inherited blood/immune cell diseases, but also for the acquired immunodeficiency syndrome. However, there is emerging evidence for substantial heterogeneity of HSCs in situ as well as ex vivo that is also observed after HSCT. Thus, HSC gene modification concepts are suggested to consider that different blood disorders affect specific hematopoietic cell types. We will discuss the relevance of HSC heterogeneity for the development and manufacture of gene therapies and in exemplary diseases with a specific emphasis on the key target HSC types myeloid-biased, lymphoid-biased, and balanced HSCs.
Background: Various studies have been made about the most effective and safest type of treatment for vertebral compression fractures (VCFs). Long-term results are needed for qualitative evaluation.
Purpose: The purpose of the study is to evaluate the effectiveness of percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP) procedures for VCFs.
Materials and Methods: Forty-nine patients who received either PVP or PKP between 2002 and 2015 returned a specially developed questionnaire and were included in a cross-sectional outcome analysis. The questionnaire assessed pain development by use of a visual analog scale (VAS). Imaging data (CT scans) were retrospectively analyzed for identification of cement leakage.
Results: Patients’ VAS scores significantly decreased after treatment (7.0 ± 3.4 => 3.7 ± 3.4), (p < 0.001). The average pain reduction in patients treated with PVP was −3.3 ± 3.8 (p < 0.001) (median −3.5) and −4.0 ± 3.9 (p < 0.001) (median −4.5) in patients treated with PKP. Fifteen Patients (41.7%) receiving PVP and four patients (30.7%) receiving PKP experienced recurrence of pain. Cement leakage occurred in 10 patients (22.73%). Patients with cement leakage showed comparable VAS scores after treatment (6.8 ± 3.5 => 1.4 ± 1.6), (p = 0.008). Thirty-nine patients reported an increase in mobility (79.6%) and 41 patients an improvement in quality of life (83.7%).
Conclusion: Pain reduction by means of PVP or PKP in patients with VCFs was discernible over the period of observation. Percutaneous vertebroplasty and PKP contribute to the desired treatment results. However, the level of low pain may not remain constant.
Pathogens possess the ability to adapt and survive in some host species but not in others–an ecological trait known as host tropism. Transmitted through ticks and carried mainly by mammals and birds, the Lyme disease (LD) bacterium is a well-suited model to study such tropism. Three main causative agents of LD, Borrelia burgdorferi, B. afzelii, and B. garinii, vary in host ranges through mechanisms eluding characterization. By feeding ticks infected with different Borrelia species, utilizing feeding chambers and live mice and quail, we found species-level differences in bacterial transmission. These differences localize on the tick blood meal, and specifically complement, a defense in vertebrate blood, and a polymorphic bacterial protein, CspA, which inactivates complement by binding to a host complement inhibitor, Factor H (FH). CspA selectively confers bacterial transmission to vertebrates that produce FH capable of allele-specific recognition. CspA is the only member of the Pfam54 gene family to exhibit host-specific FH-binding. Phylogenetic analyses revealed convergent evolution as the driver of such uniqueness, and that FH-binding likely emerged during the last glacial maximum. Our results identify a determinant of host tropism in Lyme disease infection, thus defining an evolutionary mechanism that shapes host-pathogen associations.
Purpose: Suicidality and suicidal ideation (SI) in oncology has long been an underestimated danger. Although there are cancer-specific distress screening tools available, none of these specifically incorporates items for SI. We examined the prevalence of SI in cancer patients, investigated the relation between SI and distress, and tried to identify additional associated factors. Methods: A cross-sectional study with patients treated for cancer in a primary care hospital was conducted. Psychosocial distress and SI in 226 patients was assessed. An expert rating scale (PO-Bado-SF) and a self-assessment instrument (QSC-R23) were used to measure distress. SI was assessed with item 9 of the PHQ-9. Data was descriptively analyzed, and correlations and group comparisons between clinically distressed and non-distressed patients were calculated. Results: SI was reported by 15% of patients. Classified as clinically distressed were 24.8% (QSC-R23) to 36.7% (PO-Bado-SF). SI was correlated with externally (rτ = 0.19, p < 0.001) and self-rated distress (rτ = 0.31, p < 0.001). Symptoms sufficiently severe for at least a medium major depressive episode were recorded in 23.5% of patients (PHQ-9). Factors associated with SI were feeling bad about oneself, feeling down, depressed, and hopeless, deficits in activities of daily life, psycho-somatic afflictions, social restrictions, and restrictions in daily life. Being in a steady relationship seemed to have a protective effect. Conclusions: SI is common in cancer patients. Distress and associated factors are increased in patients with SI. A distress screening with the ability to assess SI could be an important step in prevention, but more research is necessary.
Purpose: In this study, we examined distress levels and quality of life (QoL) of patients with hematologic malignancies under treatment in an acute setting. We used external- and self-assessment instruments for distress. Additionally, we investigated the relation between distress and QoL as well as whether highly distressed patients differed from less distressed patients concerning their QoL.
Methods: A cross-sectional study with patients of the Medical Clinic II of the University Hospital Frankfurt was conducted. One hundred and nine patients were assessed with an expert rating scale and completed self-report questionnaires. Data were exploratively analyzed and group comparisons between patients who scored above the cut-off of the respective screening instruments and those who did not were conducted.
Results: Patients with hematologic malignancies experience high levels of distress and low QoL. Especially, role and social functioning are affected. Patients suffer most from fatigue, appetite loss, and insomnia. Using established cut-offs, all screening instruments were able to differentiate between patients regarding distress and QoL. Patients scoring above the cut-off were significantly more distressed and had a lower QoL. There was a medium-to-strong correlation between distress and QoL indicators.
Conclusion: Cancer-specific screening instruments seem to be able to identify treatment needs more specifically. They also allowed a better differentiation concerning QoL. The close link between distress and QoL needs to be recognized to enable a holistic approach to treatment and thereby optimize the quality of treatment.
Visual search in natural scenes is a complex task relying on peripheral vision to detect potential targets and central vision to verify them. The segregation of the visual fields has been particularly established by on-screen experiments. We conducted a gaze-contingent experiment in virtual reality in order to test how the perceived roles of central and peripheral visions translated to more natural settings. The use of everyday scenes in virtual reality allowed us to study visual attention by implementing a fairly ecological protocol that cannot be implemented in the real world. Central or peripheral vision was masked during visual search, with target objects selected according to scene semantic rules. Analyzing the resulting search behavior, we found that target objects that were not spatially constrained to a probable location within the scene impacted search measures negatively. Our results diverge from on-screen studies in that search performances were only slightly affected by central vision loss. In particular, a central mask did not impact verification times when the target was grammatically constrained to an anchor object. Our findings demonstrates that the role of central vision (up to 6 degrees of eccentricities) in identifying objects in natural scenes seems to be minor, while the role of peripheral preprocessing of targets in immersive real-world searches may have been underestimated by on-screen experiments.
Purpose: The coronavirus disease 2019 (COVID-19) poses major challenges to health-care systems worldwide. This pandemic demonstrates the importance of timely access to intensive care and, therefore, this study aims to explore the accessibility of intensive care beds in 14 European countries and its impact on the COVID-19 case fatality ratio (CFR).
Methods: We examined access to intensive care beds by deriving (1) a regional ratio of intensive care beds to 100,000 population capita (accessibility index, AI) and (2) the distance to the closest intensive care unit. The cross-sectional analysis was performed at a 5-by-5 km spatial resolution and results were summarized nationally for 14 European countries. The relationship between AI and CFR was analyzed at the regional level.
Results: We found national-level differences in the levels of access to intensive care beds. The AI was highest in Germany (AI = 35.3), followed by Estonia (AI = 33.5) and Austria (AI = 26.4), and lowest in Sweden (AI = 5) and Denmark (AI = 6.4). The average travel distance to the closest hospital was highest in Croatia (25.3 min by car) and lowest in Luxembourg (9.1 min). Subnational results illustrate that capacity was associated with population density and national-level inventories. The correlation analysis revealed a negative correlation of ICU accessibility and COVID-19 CFR (r = − 0.57; p < 0.001).
Conclusion: Geographical access to intensive care beds varies significantly across European countries and low ICU accessibility was associated with a higher proportion of COVID-19 deaths to cases (CFR). Important differences in access are due to the sizes of national resource inventories and the distribution of health-care facilities relative to the human population. Our findings provide a resource for officials planning public health responses beyond the current COVID-19 pandemic, such as identifying potential locations suitable for temporary facilities or establishing logistical plans for moving severely ill patients to facilities with available beds.
Improving spatial accessibility to hospitals is a major task for health care systems which can be facilitated using recent methodological improvements of spatial accessibility measures. We used the integrated floating catchment area (iFCA) method to analyze spatial accessibility of general inpatient care (internal medicine, surgery and neurology) on national level in Germany determining an accessibility index (AI) by integrating distances, hospital beds and morbidity data. The analysis of 358 million distances between hospitals and population locations revealed clusters of lower accessibility indices in areas in north east Germany. There was a correlation of urbanity and accessibility up to r = 0.31 (p < 0.001). Furthermore, 10% of the population lived in areas with significant clusters of low spatial accessibility for internal medicine and surgery (neurology: 20%). The analysis revealed the highest accessibility for heart failure (AI = 7.33) and the lowest accessibility for stroke (AI = 0.69). The method applied proofed to reveal important aspects of spatial accessibility i.e. geographic variations that need to be addressed. However, for the majority of the German population, accessibility of general inpatient care was either high or at least not significantly low, which suggests rather adequate allocation of hospital resources for most parts of Germany.
Existing social stressor concepts disregard the variety of task-related situations at work that require skillful social behavior to maintain good social relationships while achieving certain task goals. In this article, we challenge the view that social stressors at work are solely dysfunctional aspects evoking employee ill health. Drawing from the challenge-hindrance stressor framework, we introduce the concept of social challenge stressors as a job characteristic and examine their relationships with individual well-and ill-being. In study 1, we developed a new scale for the measurement of social challenge stressors and tested the validity of the scale. Results from two independent samples indicated support for a single-factor structure and showed that social challenge stressors are distinct from related stressor concepts. Using two samples, one of which was already used to test the factor structure, we analyzed the unique contribution of social challenge stressors in predicting employee well- and ill-being. As expected, social challenge stressors were simultaneously related to psychological strain and well-being. Using time-lagged data, study 2 investigated mechanisms that may explain how social challenge stressors are linked to well-being and strain. In line with the stress-as-offense-to-self approach, we expected indirect relationships via self-esteem. Additionally, social support was expected to moderate the relationships between social stressors and self-esteem. Whereas the indirect relationships were mostly confirmed, we found no support for the buffering role of social support in the social hindrance stressors-self-esteem link. Although we found a moderation effect for social challenge stressors, results indicated a compensation model that conflicted with expectations.
The physical processes behind the production of light nuclei in heavy ion collisions are unclear. The successful theoretical description of experimental yields by thermal models conflicts with the very small binding energies of the observed states, being fragile in such a hot and dense environment. Other available ideas are delayed production via coalescence, or a cooling of the system after the chemical freeze-out according to a Saha equation, or a ‘quench’ instead of a thermal freeze-out. A recently derived prescription of an (interacting) Hagedorn gas is applied to consolidate the above pictures. The tabulation of decay rates of Hagedorn states into light nuclei allows to calculate yields usually inaccessible due to very poor Monte Carlo statistics. Decay yields of stable hadrons and light nuclei are calculated. While the scale-free decays of Hagedorn states alone are not compatible with the experimental data, a thermalized hadron and Hagedorn state gas is able to describe the experimental data. Applying a cooling of the system according to a Saha-equation with conservation of nucleon and anti-nucleon numbers leads to (nearly) temperature independent yields, thus a production of the light nuclei at temperatures much lower than the chemical freeze-out temperature is compatible with experimental data and with the statistical hadronization model.
Korrektur zu: Höllbacher, S., Wittum, G. Correction to: A sharp interface method using enriched finite elements for elliptic interface problems. Numer. Math. 147, 783 (2021). DOI: 10.1007/s00211-021-01180-0.
We present an immersed boundary method for the solution of elliptic interface problems with discontinuous coefficients which provides a second-order approximation of the solution. The proposed method can be categorised as an extended or enriched finite element method. In contrast to other extended FEM approaches, the new shape functions get projected in order to satisfy the Kronecker-delta property with respect to the interface. The resulting combination of projection and restriction was already derived in Höllbacher and Wittum (TBA, 2019a) for application to particulate flows. The crucial benefits are the preservation of the symmetry and positive definiteness of the continuous bilinear operator. Besides, no additional stabilisation terms are necessary. Furthermore, since our enrichment can be interpreted as adaptive mesh refinement, the standard integration schemes can be applied on the cut elements. Finally, small cut elements do not impair the condition of the scheme and we propose a simple procedure to ensure good conditioning independent of the location of the interface. The stability and convergence of the solution will be proven and the numerical tests demonstrate optimal order of convergence.
Drawing on insights found in both philosophy and psychology, this paper offers an analysis of hate and distinguishes between its main types. I argue that hate is a sentiment, i.e., a form to regard the other as evil which on certain occasions can be acutely felt. On the basis of this definition, I develop a typology which, unlike the main typologies in philosophy and psychology, does not explain hate in terms of patterns of other affective states. By examining the developmental history and intentional structure of hate, I obtain two variables: the replaceability/irreplaceability of the target and the determinacy/indeterminacy of the focus of concern. The combination of these variables generates the four-types model of hate, according to which hate comes in the following kinds: normative, ideological, retributive, and malicious.
Solute carrier (SLC) are related to various diseases in human and promising pharmaceutical targets but more structural and functional information on SLCs is required to expand their use for drug design and therapy. The 7-transmembrane segment inverted (7-TMIR) fold was identified for the SLC families 4, 23 and 26 in the last decade thus detailed analysis of the structure function relationship of one of these families might also yield insights for the other two. SVCT1 and SVCT2 from the SLC23 family are sodium dependent ascorbic acid transporters in human but structural analysis of the SLC23 family is exclusively based on two homologs – UraA from E. coli and UapA from A. nidulans – yielding two inward-facing and one occluded conformation. In combination with outward-facing conformations from SLC4 transporters, and additional information from the SLC26 family, an elevator transport mechanism for all 7-TMIR proteins was identified but detailed mechanistic features of the transport remain elusive due to the lack of multiple conformations from individual transporters.
To increase the understanding of 7-TMIR protein structure and function in this study, the transport mechanism of SLC23 transporters was analyzed by two strategies including selection of alpaca derived nanobodies and synthetic nanobodies against UraA as prokaryotic model protein of the SLC23 family. The second strategy involved mutagenesis of UraA at functional relevant positions regarding the conformational change during transport. Therefore, available structures of 7-TMIR proteins and less related elevator transporters were analyzed and a common motif identified – the alpha helical inter-domain linkers. The proposed rigid body movement for transport in combination with the characteristic alpha helical secondary structure of the linkers connecting both rigid bodies led to the hypothesis of functional relevance of the linkers and a conformational hinge being located in close proximity to the linkers. These positions were identified and used to modulate the biophysical properties of the transporter. Mutagenesis at three relevant positions led to loss of transport functionality and these UraA variants could be recombinantly produced and purified to further examine the underlying mechanistic effects. The variants UraAG320P and UraAP330G from the periplasmic inter-domain linker showed increased dimerization and thermal stability as well as substrate binding in solution. The substrate affinity of UraAG320P was identified to be 5-fold higher compared to the wildtype. The solvent accessibility of the substrate binding site in UraAG320P and UraAP330G revealed reduced open probability that indicated an altered conformational space compared to UraAWT. This phenomenon was analyzed in more detail by differential hydrogen-deuterium exchange mass spectrometry and the results supported the hypothesis of a reduced open probability and gave further insights into the impact of the two mutations in the periplasmic inter-domain linker in UraA.
This thesis further presents strategies for phage display selection of nanobodies with epitope bias and a post selection analysis pipeline to identify nanobodies with desired binding characteristics. Thereby, whole cell transport inhibition highlighted periplasmic epitope binders and conformational selectivity. A cytoplasmic epitope could be identified by pulldown with inside-out membrane vesicles for one cytoplasmic side binder. Thermal stabilization analysis of the target protein in differential scanning fluorometry was performed in presence of two different nanobodies to identify simultaneous binding by additional thermal stabilization respectively competition by intermediate melting temperatures. Combination of epitope information with simultaneous DSF could be used to identify the stabilization of different UraA conformations by a set of binders and presents a general nanobody selection strategy for other SLCs. Synthetic nanobodies (sybodies) were also included in the analysis pipeline and Sy45 identified as promising candidate for co-crystallization that gave rise to UraAWT crystals in several conditions in presence or absence of uracil. Similar crystals could be obtained in combination with UraAG320P that were further optimized to gain structural information on this mutant. The structure was solved by molecular replacement and the model refined at 3.1 Å resolution confirming the cytoplasmic epitope of Sy45 as predicted by the selection pipeline. The stabilized conformation was inward-facing similar to the reported UapA structure but significantly different to the previously reported inward-facing structure of UraA. The structure further confirmed the structural integrity of the UraA mutant G320P. Despite the monomeric state of UraA in the structure, the gate domain aligned reasonably well with the gate domain of the previously published dimeric UraA structure in the occluded conformation and allowed detailed analysis of the conformational transition in UraA from inward-facing to occluded by a single rigid body movement. Thereby little movement in the gate domain of UraA was observed in contrast to a previously reported transport mechanism. Core domain rotation around a rotation axis parallel to the substrate barrier was found to explain the major part of conformational transition from inward-facing to occluded and experimentally supported the hypothesized mechanism by Chang et al. (2017). Additionally, the conformational hinge around position G320 in UraA could be identified as well as the impact of the backbone rigidity introduced by the highly conserved proline residue at position 330 in UraA on the conformational transition. This position was found to serve as anchoring point the inter-domain linker and determines the coordinated movement of inter-domain linker and core domain. The functional analysis further highlighted the requirement of alpha helical secondary structure within the inter-domain linker that serves as amphipathic structural entity that can adjust to changed core-gate domain distances and angles during transport by extension/compression or bending while preserving the rigid linkage.
The applied strategies to modulate the conformational space of UraA by mutagenesis at the hinge positions in the inter-domain linkers is transferrable to other transporters and might facilitate their structural and functional characterization.
Further, this study discusses the conformational thermostabilization of UraA that is based on increased melting temperatures upon restriction of its conformational freedom. The term ‘conformational thermostabilization’ introduced by Serrano-Vega et al. (2007) could be experimentally supported and the direct correlation between the conformational freedom and thermostabilization was qualitatively analyzed for UraA. The concept of conformational thermostabilization might help in characterization of other dynamic transport systems as well.
We derive a simple criterion that ensures uniqueness, Lipschitz stability and global convergence of Newton’s method for the finite dimensional zero-finding problem of a continuously differentiable, pointwise convex and monotonic function. Our criterion merely requires to evaluate the directional derivative of the forward function at finitely many evaluation points and for finitely many directions. We then demonstrate that this result can be used to prove uniqueness, stability and global convergence for an inverse coefficient problem with finitely many measurements. We consider the problem of determining an unknown inverse Robin transmission coefficient in an elliptic PDE. Using a relation to monotonicity and localized potentials techniques, we show that a piecewise-constant coefficient on an a-priori known partition with a-priori known bounds is uniquely determined by finitely many boundary measurements and that it can be uniquely and stably reconstructed by a globally convergent Newton iteration. We derive a constructive method to identify these boundary measurements, calculate the stability constant and give a numerical example.
Bloodstream infections (BSI) are a frequent complication in patients with hematological and oncological diseases. However, the impact of different bacterial species causing BSI and of multiple BSI remains incompletely understood. We performed a retrospective study profiling 637 bacterial BSI episodes in hematological and oncological patients. Based on the 30-day (30d) overall survival (OS), we analyzed different types of multiple BSI and grouped BSI-associated bacteria into clusters followed by further assessment of clinical and infection-related characteristics. We discovered that polymicrobial BSI (different organisms on the first day of a BSI episode) and sequential BSI (another BSI before the respective BSI episode) were associated with a worse 30d OS. Different bacterial groups could be classified into three BSI outcome clusters based on 30d OS: favorable (FAV) including mainly common skin contaminants, Escherichia spp. and Streptococcus spp.; intermediate (INT) including mainly Enterococcus spp., vancomycin-resistant Enterococcus spp., and multidrug-resistant gram-negative bacteria (MDRGN); and adverse (ADV) including MDRGN with an additional carbapenem-resistance (MDRGN+CR). A polymicrobial or sequential BSI especially influenced the outcome in the combination of two INT cluster BSI. The presence of a polymicrobial BSI and the assignment into the BSI outcome clusters were identified as independent risk factors for 30d mortality in a Cox multivariate regression analysis. The assignment to a BSI outcome cluster and the differentiated perspective of multiple BSI open new insights into the prognosis of patients with BSI and should be further validated in other patient cohorts.
Background: The environmental impact of pesticides has been an increasingly discussed issue over the last decades. Constant usage of pesticides presents a burden for soil and causes a decrease in its health, including the negative effects on earthworms which are indicators for soil quality. The objective of this research was the assessment of the effects of two insecticides and two herbicides on the earthworm Eisenia andrei. Namely, the following active ingredients and respective commercial preparations were investigated: esfenvalerate (Sumialfa), thiacloprid (Calypso), dimethenamid-p (Frontier) and prosulfocarb (Filon). Lethal concentrations (48 h) of both active ingredient and commercial preparations were determined using the filter paper contact test. Results: The results showed that Calypso and Frontier were significantly more toxic than the active ingredient. Therefore, all further measurements were performed after exposure of earthworms to the commercial preparations of the pesticides. Specifically, several enzymatic biomarkers and multixenobiotic resistance activity were assessed. Additionally, a fluorescence-based assay for the determination of oxidative stress was established. Significant changes were detected for catalase, carboxylesterase and multixenobiotic activities after 48-h exposures. Also, a significant change in oxidative stress parameters could be observed for both Calypso and Frontier. Conclusions: The obtained results show that commercial preparations can be more toxic than the active ingredients, and the formulations being distributed in the environment can affect earthworms on a molecular level already after short exposures. This emphasizes the importance of a more integrated eco-toxicological assessment of commercial pesticide preparations not to underestimate their effects on the environment.
Several novel imaging and non-destructive testing technologies are based on reconstructing the spatially dependent coefficient in an elliptic partial differential equation from measurements of its solution(s). In practical applications, the unknown coefficient is often assumed to be piecewise constant on a given pixel partition (corresponding to the desired resolution), and only finitely many measurement can be made. This leads to the problem of inverting a finite-dimensional non-linear forward operator F: D(F)⊆Rn→Rm , where evaluating ℱ requires one or several PDE solutions.
Numerical inversion methods require the implementation of this forward operator and its Jacobian. We show how to efficiently implement both using a standard FEM package and prove convergence of the FEM approximations against their true-solution counterparts. We present simple example codes for Comsol with the Matlab Livelink package, and numerically demonstrate the challenges that arise from non-uniqueness, non-linearity and instability issues. We also discuss monotonicity and convexity properties of the forward operator that arise for symmetric measurement settings.
This text assumes the reader to have a basic knowledge on Finite Element Methods, including the variational formulation of elliptic PDEs, the Lax-Milgram-theorem, and the Céa-Lemma. Section 3 also assumes that the reader is familiar with the concept of Fréchet differentiability.
Purpose: Perfusion-weighted MRI (PWI) and O-(2-[18F]fluoroethyl-)-l-tyrosine ([18F]FET) PET are both applied to discriminate tumor progression (TP) from treatment-related changes (TRC) in patients with suspected recurrent glioma. While the combination of both methods has been reported to improve the diagnostic accuracy, the performance of a sequential implementation has not been further investigated. Therefore, we retrospectively analyzed the diagnostic value of consecutive PWI and [18F]FET PET.
Methods: We evaluated 104 patients with WHO grade II–IV glioma and suspected TP on conventional MRI using PWI and dynamic [18F]FET PET. Leakage corrected maximum relative cerebral blood volumes (rCBVmax) were obtained from dynamic susceptibility contrast PWI. Furthermore, we calculated static (i.e., maximum tumor to brain ratios; TBRmax) and dynamic [18F]FET PET parameters (i.e., Slope). Definitive diagnoses were based on histopathology (n = 42) or clinico-radiological follow-up (n = 62). The diagnostic performance of PWI and [18F]FET PET parameters to differentiate TP from TRC was evaluated by analyzing receiver operating characteristic and area under the curve (AUC).
Results: Across all patients, the differentiation of TP from TRC using rCBVmax or [18F]FET PET parameters was moderate (AUC = 0.69–0.75; p < 0.01). A rCBVmax cutoff > 2.85 had a positive predictive value for TP of 100%, enabling a correct TP diagnosis in 44 patients. In the remaining 60 patients, combined static and dynamic [18F]FET PET parameters (TBRmax, Slope) correctly discriminated TP and TRC in a significant 78% of patients, increasing the overall accuracy to 87%. A subgroup analysis of isocitrate dehydrogenase (IDH) mutant tumors indicated a superior performance of PWI to [18F]FET PET (AUC = 0.8/< 0.62, p < 0.01/≥ 0.3).
Conclusion: While marked hyperperfusion on PWI indicated TP, [18F]FET PET proved beneficial to discriminate TP from TRC when PWI remained inconclusive. Thus, our results highlight the clinical value of sequential use of PWI and [18F]FET PET, allowing an economical use of diagnostic methods. The impact of an IDH mutation needs further investigation.
This paper contributes to the clarification of the concept of “typicality” discussed in contemporary philosophy of physics by conceiving the nomological status of a typical behaviour such as that expressed in the Second Law of Thermodynamics as a “minutis rectis law”. A brief sketch of the discovery of “typicality” shows that there were ideas of typical behaviour not only in physics but also in sociology. On this basis and in analogy to the Second Law of Thermodynamics, it is shown that the nomological status of sociological laws such as Gresham’s Law can also be conceived as “minutis rectis laws”.
India has recorded 142,186 deaths over 36 administrative regions placing India third in the world after the US and Brazil for COVID-19 deaths as of 12 December 2020. Studies indicate that south-west monsoon season plays a role in the dynamics of contagious diseases, which tend to peak post-monsoon season. Recent studies show that vitamin D and its primary source Ultraviolet-B (UVB) radiation may play a protective role in mitigating COVID-19 deaths. However, the combined roles of the monsoon season and UVB radiation in COVID-19 in India remain still unclear. In this observational study, we empirically study the respective roles of monsoon season and UVB radiation, whilst further exploring, whether the monsoon season negatively impacts the protective role of UVB radiation in COVID-19 deaths in India. We use a log-linear Mundlak model to a panel dataset of 36 administrative regions in India from 14 March 2020–19 November 2020 (n = 6751). We use the cumulative COVID-19 deaths as the dependent variable. We isolate the association of monsoon season and UVB radiation as measured by Ultraviolet Index (UVI) from other confounding time-constant and time-varying region-specific factors. After controlling for various confounding factors, we observe that a unit increase in UVI and the monsoon season are separately associated with 1.2 percentage points and 7.5 percentage points decline in growth rates of COVID-19 deaths in the long run. These associations translate into substantial relative changes. For example, a permanent unit increase of UVI is associated with a decrease of growth rates of COVID-19 deaths by 33% (= − 1.2 percentage points) However, the monsoon season, mitigates the protective role of UVI by 77% (0.92 percentage points). Our results indicate a protective role of UVB radiation in mitigating COVID-19 deaths in India. Furthermore, we find evidence that the monsoon season is associated with a significant reduction in the protective role of UVB radiation. Our study outlines the roles of the monsoon season and UVB radiation in COVID-19 in India and supports health-related policy decision making in India.
Background: Studies of parasite communities and patterns in the Antarctic are an important knowledge base with the potential to track shifts in ecological relations and study the effects of climate change on host–parasite systems. Endemic Nototheniinae is the dominant fish group found in Antarctic marine habitats. Through their intermediate position within the food web, Nototheniinae link lower to higher trophic levels and thereby also form an important component of parasite life cycles. The study was set out to gain insight into the parasite fauna of Nototheniops larseni, N. nudifrons and Lepidonotothen squamifrons (Nototheniinae) from Elephant Island (Antarctica).
Methods: Sampling was conducted at three locations around Elephant Island during the ANT-XXVIII/4 expedition of the research vessel Polarstern. The parasite fauna of three Nototheniine species was analysed, and findings were compared to previous parasitological and ecological research collated from a literature review.
Results: All host species shared the parasites Neolebouria antarctica (Digenea), Corynosoma bullosum (Acanthocephala) and Pseudoterranova decipiens E (Nematoda). Other parasite taxa were exclusive to one host species in this study. Nototheniops nudifrons was infected by Ascarophis nototheniae (Nematoda), occasional infections of N. larseni with Echinorhynchus petrotschenkoi (Acanthocephala) and L. squamifrons with Elytrophalloides oatesi (Digenea) and larval tetraphyllidean Cestoda were detected.
Conclusion: All examined fish species’ parasites were predominantly euryxenous regarding their fish hosts. The infection of Lepidonotothen squamifrons with Lepidapedon garrardi (Digenea) and Nototheniops larseni with Echinorhynchus petrotschenkoi represent new host records. Despite the challenges and limited opportunities for fishing in remote areas, future studies should continue sampling on a more regular basis and include a larger number of fish species and sampling sites within different habitats.
Self-compassion has been theorized to have three components, each with a positive pole and a negative pole: self-kindness versus self-judgment, common humanity versus isolation, and mindfulness versus over-identification. Neff (Self Identity 2:85–101, 2003a) proposes that they mutually influence each other, however, this proposition has not been tested yet. We conducted a pilot study to see if improvements from training one component spilled over to the other two—and whether these trainings had an impact on well-being. 80 participants completed 8 weeks of self-compassionate writing exercises to enhance either self-kindness, common humanity, or mindfulness. Trait self-compassion was assessed using the six-factor model of the self-compassion scale. To address issues of alpha-error-inflation, the false discovery rate was fixed at 5%, and critical p values were adjusted accordingly. Participants in the mindfulness condition reported increased total self-compassion (p = .009), which was accompanied by increased self-kindness (p = .027) and lower isolation (p = .045). Participants in the common humanity condition reported improved total self-compassion (p = .018), lower over-identification (p = .045), and higher life-satisfaction (p = .049). The training in self-kindness failed to improve self-kindness or any other factor. These findings provide initial evidence that the components of self-compassion mutually enhance each other. They also emphasize the importance of mindfulness within the conceptualization of self-compassion.
Aims: The purpose of this paper was to investigate the relationship between high-involvement human resource management, autonomy, affective organisational commitment and innovative behaviours of nursing staff who care for elderly clients.
Background: Nursing teams are increasingly required to demonstrate innovative behaviours that enhance care quality. Nursing leaders need to create environments where nursing staff have sufficient autonomy and feel a sense of commitment to support these behaviours. The appropriate implementation of these processes and practices may lead to greater involvement.
Methods: A cross-sectional survey-based research design was employed to explore the experiences of involvement practices, autonomy, affective organisational commitment and innovative behaviours of 567 nursing staff workers from four elderly care organisations in the Netherlands.
Results: The results demonstrate that a bundle of high-involvement practices positively influences innovative behaviour and that affective commitment and autonomy fully mediate this relationship.
Conclusions: The study highlights the role of autonomy and commitment as routes towards translating involvement practices into nurses’ innovativeness.
Implications for Nursing Management: To create an innovative environment, leaders need to create a positive climate by providing nurses with opportunities to enhance their competence, relatedness and autonomy through active involvement. Leaders should, therefore, encourage involvement as a mechanism to promote innovation.
Analyses of species functional traits are suitable to better understand the coexistence of species in a given environment. Trait information can be applied to investigate diversity patterns along environmental gradients and subsequently to predict and mitigate threats associated with climate change and land use. Species traits are used to calculate community trait means, which can be related to environmental gradients. However, while species traits can provide insights into the mechanisms underlying community assembly, they can lead to erroneous inferences if mean trait values are used. An alternative is to incorporate intraspecific trait variability (ITV) into calculating the community trait means. This approach gains increasing acceptance in plant studies. For macrofungi, functional traits have recently been applied to examine their community ecology but, to our knowledge, ITV has yet to be incorporated within the framework of community trait means. Here, we present a conceptual summary of the use of ITV to investigate the community ecology of macrofungi, including the underlying ecological theory. Inferences regarding community trait means with or without the inclusion of ITV along environmental gradients are compared. Finally, an existing study is reconsidered to highlight the variety of possible outcomes when ITV is considered. We hope this Opinion will increase awareness of the potential for within-species trait variability and its importance for statistical inferences, interpretations, and predictions of the mechanisms structuring communities of macro- and other fungi.
The hot and dense QCD matter produced in nuclear collisions at ultrarelativistic energy is characterized by very intense electromagnetic fields which attain their maximal strength in the early pre-equilibrium stage and interplay with the strong vorticity induced in the plasma by the large angular momentum of the colliding system. A promising observable keeping trace of these phenomena is the directed flow of light hadrons and heavy mesons produced in symmetric and asymmetric heavy-ion collisions as well as in proton-induced reactions. In particular, the splitting of the directed flow between particles with the same mass but opposite electric charge as a function of rapidity and transverse momentum gives access to the electromagnetic response of medium in all collision stages and in the different colliding systems. The highest influence of the electromagnetic fields is envisaged in the pre-equilibrium stage of the collision and therefore a significant imprint is left on the early-produced heavy quarks. The aim of this review is to discuss the current developments towards the understanding of the generation and relaxation time of the electromagnetic fields embedded in both large and small systems and their impact on the charge-odd directed flow of light and heavy particles, highlighting the experimental results and the different theoretical approaches. Since it is possible to perform realistic simulations of high-energy collisions that incorporate also the generated electromagnetic fields and vorticity, the study of the directed flow can provide unique insight into the early nonequilibrium phase and the ensuing QGP formation and transport properties.
This focus issue of the European Journal of Trauma and Emergency Surgery compiles a collection of outstanding clinical research using the immense dataset of the German TraumaRegister DGU® (TR-DGU). The TR-DGU of the German Trauma Society (Deutsche Gesellschaft für Unfallchirurgie, DGU) was founded in 1993. Currently, approximately 40,000 cases from more than 600 hospitals are entered into the database every year. The selected articles of this focus on issue highlight the immense value the TR-DGU constitutes for the current, but also for the future trauma research.
Shares of open-end real estate funds are typically traded directly between the investor and the fund management company. However, we provide empirical evidence for the growth of secondary market activities, i.e., the trading of shares on stock exchanges. We find high trading levels in situations where the fund management company suspends the issue or redemption of shares. Shares trade at a discount when the fund management company suspends the redemption, whereas shares trade at a premium when the fund management company suspends the issue. We also find evidence that secondary market trading activity is increasing since German regulation introduced a minimum holding period and a mandatory notice period for open-end real estate funds.
Introduction: The induced membrane technique for the treatment of large bone defects is a two-step procedure. In the first operation, a foreign body membrane is induced around a spacer, then, in the second step, several weeks or months later, the spacer is removed and the Membrane pocket is filled with autologous bone material. Induction of a functional biological membrane might be avoided by initially using a biological membrane. In this study, the effect of a human acellular dermis (hADM, Epiflex, DIZG gGmbH) was evaluated for the treatment of a large (5 mm), plate-stabilised femoral bone defect.
Material and Methods: In an established rat model, hADM was compared to the two-stage induced membrane technique and a bone defect without membrane cover. Syngeneous spongiosa from donor animals was used for defect filling in all groups. The group size in each case was n = 5, the induction time of the membrane was 3–4 weeks and the healing time after filling of the defect was 8 weeks.
Results: The ultimate loads were increased to levels comparable with native bone in both membrane groups (hADM: 63.2% ± 29.6% of the reference bone, p < 0.05 vs. no membrane, induced membrane: 52.1% ± 25.8% of the reference bone, p < 0.05 vs. no membrane) and were significantly higher than the control group without membrane (21.5%). The membrane groups were radiologically and histologically almost completely bridged by new bone formation, in contrast to the control Group where no closed osseous bridging could be observed.
Conclusion: The use of the human acellular dermis leads to equivalent healing results in comparison to the two-stage induced membrane technique. This could lead to a shortened therapy duration of large bone defects.
The relativistic treatment of spin is a fundamental subject which has an old history. In various physical contexts it is necessary to separate the relativistic total angular momentum into an orbital and spin contribution. However, such decomposition is affected by ambiguities since one can always redefine the orbital and spin part through the so-called pseudo-gauge transformations. We analyze this problem in detail by discussing the most common choices of energy-momentum and spin tensors with an emphasis on their physical implications, and study the spin vector which is a pseudo-gauge invariant operator. We review the angular momentum decomposition as a crucial ingredient for the formulation of relativistic spin hydrodynamics and quantum kinetic theory with a focus on relativistic nuclear collisions, where spin physics has recently attracted significant attention. Furthermore, we point out the connection between pseudo-gauge transformations and the different definitions of the relativistic center of inertia. Finally, we consider the Einstein–Cartan theory, an extension of conventional general relativity, which allows for a natural definition of the spin tensor.
We show that the metrisability of an oriented projective surface is equivalent to the existence of pseudo-holomorphic curves. A projective structure p and a volume form σ on an oriented surface M equip the total space of a certain disk bundle Z→M with a pair (Jp,Jp,σ) of almost complex structures. A conformal structure on M corresponds to a section of Z→M and p is metrisable by the metric g if and only if [g]:M→Z is a pseudo-holomorphic curve with respect to Jp and Jp,dAg.
Disagreement among philosophers over the proper justification for political institutions is far from a new phenomenon. Thus, it should not come as a surprise that there is substantial room for dissent on this matter within democratic theory. As is well known, instrumentalism and proceduralism represent the two primary viewpoints that democrats can adopt to vindicate democratic legitimacy. While the former notoriously derives the value of democracy from its outcomes, the latter claims that a democratic decision-making process is inherently valuable. This article has two aims. First, it introduces three variables with which we can thoroughly categorise the aforementioned approaches. Second, it argues that the more promising version of proceduralism is extrinsic, rather than intrinsic, and that extrinsically procedural accounts can appeal to other values in the justification of democracy without translating into instrumentalism. This article is organised as follows. I present what I consider to be the ‘implicit view’ in the justification of democracy. Then, I analyse each of the three variables in a different section. Finally, I raise an objection against procedural views grounded in relational equality, which cannot account for the idea that democracy is a necessary condition for political legitimacy.
Non-ribosomal peptide synthetases (NRPSs) are large multienzyme machineries. They synthesize numerous important natural products starting from amino acids. For peptide synthesis functionally specialized NRPS modules interact in a defined manner. Individual modules are either located on a single or on multiple different polypeptide chains. The “peptide-antimicrobial-Xenorhabdus” (PAX) peptide producing NRPS PaxS from Xenorhabdus bacteria consists of the three proteins PaxA, PaxB and PaxC. Different docking domains (DDs) located at the N-termini of PaxB and PaxC and at the C-termini of PaxA and BaxB mediate specific non-covalent interactions between them. The N-terminal docking domains precede condensation domains while the C-terminal docking domains follow thiolation domains. The binding specificity of individual DDs is important for the correct assembly of multi-protein NRPS systems. In many multi-protein NRPS systems the docking domains are sufficient to mediate the necessary interactions between individual protein chains. However, it remains unclear if this is a general feature for all types of structurally different docking domains or if the neighboring domains in some cases support the function of the docking domains. Here, we report the 1H, 13C and 15 N NMR resonance assignments for a C-terminal di-domain construct containing a thiolation (T) domain followed by a C-terminal docking domain (CDD) from PaxA and for its binding partner – the N-terminal docking domain (NDD) from PaxB from the Gram-negative entomopathogenic bacterium Xenorhabdus cabanillasii JM26 in their free states and for a 1:1 complex formed by the two proteins. These NMR resonance assignments will facilitate further structural and dynamic studies of this protein complex.
Consider two independent random walks. By chance, there will be spells of association between them where the two processes move in the same direction, or in opposite direction. We compute the probabilities of the length of the longest spell of such random association for a given sample size, and discuss measures like mean and mode of the exact distributions. We observe that long spells (relative to small sample sizes) of random association occur frequently, which explains why nonsense correlation between short independent random walks is the rule rather than the exception. The exact figures are compared with approximations. Our finite sample analysis as well as the approximations rely on two older results popularized by Révész (Stat Pap 31:95–101, 1990, Statistical Papers). Moreover, we consider spells of association between correlated random walks. Approximate probabilities are compared with finite sample Monte Carlo results.
The aim of this paper is to take a fresh look at a discussion about the distinct existences argument that took place between David Armstrong and Frank Jackson more than 50 years ago. I will try to show that Armstrong’s argument can be successfully defended against Jackson’s objections (albeit at the price of certain concessions concerning Armstrong’s view on the meaning of psychological terms as well as his conception of universals). Focusing on two counterexamples that Jackson put forward against Hume’s principle (which is central to Armstrong’s argument), I will argue that they are either compatible with Hume’s principle, or imply a false claim. I will also look at several other considerations that go against Hume’s principle, such as, for example, Kripke’s origin essentialism and counterexamples from aposteriori necessity.
Aims: SARS-CoV-2 is a single-stranded RNA virus which is part of the ß-coronavirus family (like SARS 2002 and MERS 2012). The high prevalence of hospitalization and mortality, in addition to the lack of vaccines and therapeutics, forces scientists and clinicians around the world to evaluate new therapeutic options. One strategy is the repositioning of already known drugs, which were approved drugs for other indications.
Subject and method: SARS-CoV-2 entry inhibitors, RNA polymerase inhibitors, and protease inhibitors seem to be valuable targets of research. At the beginning of the pandemic, the ClinicalTrials.gov webpage listed n=479 clinical trials related to the antiviral treatment of SARS-CoV-2 (01.04.2020, “SARS-CoV-2,” “COVID-19,” “antivirals,” “therapy”), of which n=376 are still accessible online in January 2021 (10.01.2021). Taking into account further studies not listed in the CTG webpage, this narrative review appraises HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors as promising candidates for the treatment of COVID-19.
Results: Lopinavir/ritonavir, darunavir/cobicistat, remdesivir, tenofovir-disoproxilfumarate, favipriravir, and sofosbuvir are evaluated in clinical studies worldwide. Study designs show a high variability and results often are contradictory. Remdesivir is the drug, which is deployed in nearly 70% of the reviewed clinical trials, followed by lopinavir/ritonavir, favipiravir, ribavirine, and sofosbuvir.
Discussion: This review discusses the pharmacological/clinical background and questions the rationale and study design of clinical trials with already approved HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors which are repositioned during the SARS-CoV-2 pandemic worldwide. Proposals are made for future study design and drug repositioning of approved antiretroviral compounds.
Background: The prevalence of multimorbidity is increasing in recent years, and patients with multimorbidity often have a decrease in quality of life and require more health care. The aim of this study was to explore the evolution of multimorbidity taking the sequence of diseases into consideration.
Methods: We used a Belgian database collected by extracting coded parameters and more than 100 chronic conditions from the Electronic Health Records of general practitioners to study patients older than 40 years with multiple diagnoses between 1991 and 2015 (N = 65 939). We applied Markov chains to estimate the probability of developing another condition in the next state after a diagnosis. The results of Weighted Association Rule Mining (WARM) allow us to show strong associations among multiple conditions.
Results: About 66.9% of the selected patients had multimorbidity. Conditions with high prevalence, such as hypertension and depressive disorder, were likely to occur after the diagnosis of most conditions. Patterns in several disease groups were apparent based on the results of both Markov chain and WARM, such as musculoskeletal diseases and psychological diseases. Psychological diseases were frequently followed by irritable bowel syndrome.
Conclusions: Our study used Markov chains and WARM for the first time to provide a comprehensive view of the relations among 103 chronic conditions, taking sequential chronology into consideration. Some strong associations among specific conditions were detected and the results were consistent with current knowledge in literature, meaning the approaches were valid to be used on larger data sets, such as National Health care Systems or private insurers.
The current pandemic situation caused by the Betacoronavirus SARS-CoV-2 (SCoV2) highlights the need for coordinated research to combat COVID-19. A particularly important aspect is the development of medication. In addition to viral proteins, structured RNA elements represent a potent alternative as drug targets. The search for drugs that target RNA requires their high-resolution structural characterization. Using nuclear magnetic resonance (NMR) spectroscopy, a worldwide consortium of NMR researchers aims to characterize potential RNA drug targets of SCoV2. Here, we report the characterization of 15 conserved RNA elements located at the 5′ end, the ribosomal frameshift segment and the 3′-untranslated region (3′-UTR) of the SCoV2 genome, their large-scale production and NMR-based secondary structure determination. The NMR data are corroborated with secondary structure probing by DMS footprinting experiments. The close agreement of NMR secondary structure determination of isolated RNA elements with DMS footprinting and NMR performed on larger RNA regions shows that the secondary structure elements fold independently. The NMR data reported here provide the basis for NMR investigations of RNA function, RNA interactions with viral and host proteins and screening campaigns to identify potential RNA binders for pharmaceutical intervention.
I will argue for a novel variant of the knowledge norm for practical reasoning. In Sect. 2, I will look at current variations of a knowledge norm for practical reasoning and I will provide reasons to doubt these proposals. In Sects. 3 and 4, I develop my own proposal according to which knowledge is the norm of apt practical reasoning. Section 5 considers objections. Finally, Sect. 6 concerns the normativity of my proposed knowledge norm and its significance.
Despite all advancements in cancer research and clinical practice, cancer remains a life- threatening disease with an increasing incidence. According to a 2018 WHO forecast, cancer incidence will double to approximately 37 million new cancer cases by 2040. Today, clinical management of cancer is based on a "one-fits-all" strategy. Most cancers are still treated by surgical therapy followed by adjuvant or neoadjuvant chemotherapy based on rather strict guidelines (S3 guidelines in Europe) which are based on studies of large cohorts of patients with the same tumor entity. While this approach has led to substantial increases in progression-free survival and overall patient survival, most patients do not benefit from the administered treatment regimen. One reason for this is intra-tumor heterogeneity, which results from clonal evolution between cancer cells and their environment. This means that cancer patients may respond differently to a particular drug due to the different mutation patterns of their tumor cells. Therefore, patients should be screened in advance for reliable cancer biomarkers that definitively predict whether they will respond to a particular therapy. This would increase the probability of a successful treatment.
Colorectal cancer (CRC) is the third most diagnosed cancer and the second leading cause of cancer deaths worldwide. The main cause of death in CRC is a metastatic disease, which is presented in 20 % of patients and eventually develops in more than 30 % of early-stage patients. Despite the significant increase (to more than 30 months) in median survival with the development of cytotoxic agents and the introduction of targeted therapy, the progression-free survival in the first-line setting has remained largely unchanged over the past decade.
The heterogeneity in CRC is characterized by alterations in multiple signaling pathways that affect cellular functions such as cell proliferation or apoptosis. Commonly affected signaling pathways include the mitogen-activated protein kinase (MAPK)- and the transforming growth factor-β/bone morphogenetic protein (TGF-β/BMP)-pathway. Alterations in the TGF-β/BMP pathway, due to mutations in the SMAD4 gene (mothers against decapentaplegic homolog 4), are associated with different drug response and promote resistance to chemotherapy. In addition, they are associated with a higher recurrence rate.
SMAD4 is one of the most common cancer driver genes, and mutations occur in up to 15 % of CRC cases. Therefore, there is an urgent need for therapeutic agents that can specifically target SMAD4-mutated tumors.
The aim of the present study was the identification of the clinical relevance of the SMAD4 gene and the investigation of its suitability as a potential biomarker in CRC.
For this purpose, I investigated sibling patient-derived organoids (PDOs) derived from different regions of a chemo-naïve CRC tumor. PDOs are 3D cell cultures that reliably recapitulate the architecture of the tissue of origin, as well as preserve the genomic background and intra-tumor heterogeneity. The sibling PDOs (R1R361H and R4wt) shared the most common CRC mutations, such as KRASG12D (kirsten rat sarcoma), PIK3CAH1047R (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha), and TP53C242F (tumor protein 53), but differed in a SMAD4R361H mutation and showed a different drug response. The single nucleotide variant R361H of the SMAD4 gene is among the most common pathogenic alterations in various cancers, including CRC.
The sibling PDOs showed significant differences in response to the MEK-inhibitors cobimetinib, trametinib, and selumetinib. MEK-inhibitors are antineoplastic agents that inhibit the function of MEK1 and MEK2, preventing phosphorylation of transcription factors, which leads to inhibition of tumor cell proliferation. MEK-inhibitors are approved for the treatment of malignant melanoma. Currently, they are in phase-III clinical trials for the treatment of patients with metastatic CRC.
To investigate whether SMAD4R361H is responsible for sensitivity to MEK-inhibitors, Iestablished three syngeneic PDOs harboring a SMAD4R361H mutation using the CRISPR/Cas9 genome editing system. All CRISPR-PDOs were significantly more sensitive to the MEK-inhibitors, compared to R4wt. I have shown that the SMAD4R361H mutation is responsible for sensitivity to MEK inhibition in CRC models and may be a predictive biomarker.
To test this hypothesis, I examined 62 CRC PDO models and treated them with the MEK-inhibitors cobimetinib, trametinib, and selumetinib. All models that had a pathogenic mutation or deletion in the SMAD4 gene (15 %) were sensitive to cobimetinib, 10 % of models were sensitive to trametinib, and 8 % were sensitive to selumetinib.
I performed transcriptome (RNA sequencing) and proteome analyses using the DigiWest® method to investigate the mechanism underlying MEK-inhibitor sensitivity.
DigiWest® is a Luminex® bead-based analysis that allows the simultaneous analysis of over 100 (phospho-)proteins. The transcriptome and proteome data support the observation that MEK inhibition primarily affects SMAD4R361H PDOs. Furthermore, I have shown that activation of the BMP signaling pathway in organoids with wild-type SMAD4 appears to be responsible for resistance to MEK-inhibitors. Thus, a genetic alteration in the BMP signaling pathway, beyond SMAD4, could lead to sensitivity to MEK-inhibitors.
I identified four genes involved in the TGF-β/BMP signaling pathway that are frequently mutated in CRC and grouped them into the so-called SFAB-signature (SMAD4, FBXW7 (F-box/WD repeat-containing protein 7), ARID1A (AT-rich interactive domain-containing protein 1A), or BMPR2 (Bone morphogenetic protein receptor type II). Clinical data show that approximately 36 % of CRC patients have at least one pathogenic mutation in these genes.
I tested all 62 CRC PDO models and found a significant positive prediction for sensitivity to cobimetinib (95 %) and selumetinib (70 %) for the SFAB-signature. Trametinib and the newly approved MEK-inhibitor binimetinib showed a similar trend. Therefore, the SFAB-signature has high predictive power for response to MEK-inhibitors and could be used as a predictive biomarker panel.
The current clinically used biomarkers for CRC are based on the mutation status of driver genes KRAS and BRAF, which are present in up to 50 % and 10 % of CRC, respectively. Investigation of molecular alterations in CRC revealed that mutations in the KRAS gene, which is downstream of EGFR (epidermal growth factor receptor) in the MAPK-pathway, interfere with an anti-EGFR-antibody therapy (e.g., cetuximab). Therefore, cetuximab is only relevant for RAS wild-type tumors. However, approximately 40 % of patients with RAS wild-type status do not respond to this treatment.
About 53 % of CRC PDO models carry a pathogenic RAS mutation, about 10 % harbor a pathogenic BRAF mutation. Both, the RAS and RAF status alone as well as the combination of RAS and RAF status with SFAB-signature did not provide a better prediction of sensitivity to MEK inhibition.
Aqueous solutions of a nonionic surfactant (either Tween20 or BrijL23) and an anionic surfactant (sodium dodecyl sulfate, SDS) are investigated, using small-angle neutron scattering (SANS). SANS spectra are analysed by using a core-shell model to describe the form factor of self-assembled surfactant micelles; the intermicellar interactions are modelled by using a hard-sphere Percus–Yevick (HS-PY) or a rescaled mean spherical approximation (RMSA) structure factor. Choosing these specific nonionic surfactants allows for comparison of the effect of branched (Tween20) and linear (BrijL23) surfactant headgroups, both constituted of poly-ethylene oxide (PEO) groups. The nonionic–anionic surfactant mixtures are studied at various concentrations up to highly concentrated samples (ϕ ≲ 0.45) and various mixing ratios, from pure nonionic to pure anionic surfactant solutions. The scattering data reveal the formation of mixed micelles already at concentrations below the critical micelle concentration of SDS. At higher volume fractions, excluded volume effects dominate the intermicellar structuring, even for charged micelles. In consequence, at high volume fractions, the intermicellar structuring is the same for charged and uncharged micelles. At all mixing ratios, almost spherical mixed micelles form. This offers the opportunity to create a system of colloidal particles with a variable surface charge. This excludes only roughly equimolar mixing ratios (X≈ 0.4–0.6) at which the micelles significantly increase in size and ellipticity due to specific sulfate–EO interactions.
While B-cell acute lymphoblastic leukaemia (B-ALL) can be described as the leukaemia of childhood, chronic myeloid leukaemia (CML) mostly develops in elderly individuals. Understanding and utilising mechanisms involved in the development and persistence of these leukaemias as possible targets for treatment strategies has received particular interest. Processes that happen in the vicinity of the cancerous cells themselves could influence cancer growth and behaviour and hence can serve as novel targets, leading to the development of two-pronged therapies that act both on leukaemic cells directly as well as their niche. The niche in the case of leukaemia is the bone marrow microenvironment (BMM) where these cells are not only generated but also instructed and protected. As the BMM is situated inside bones that undergo drastic changes and growth processes during the ageing process, the BMM itself is also being altered throughout life. These alterations and the very process of expansion itself may therefore also provide distinct regulatory influences on the cells (healthy or malignant) that are generated inside this niche, leading to the question: Does the age of the bone marrow microenvironment differentially influence the development of (“childhood”) B-ALL versus (“adult”) CML by the release of cytokines?
In previous studies by the host-laboratory the age distribution of B-ALL versus CML in a murine transduction/ transplantation model could be recapitulated; young mice which received the same number of leukaemia-initiating cells as their old counterparts died significantly earlier of B-ALL while showing a significantly delayed clinical course, when they were suffering from CML. The tumour load and other leukaemia-associated parameters also showed a clear disposition towards preferential induction of CML in elderly and B-ALL in younger mice.
In this project we could support the hypothesis that the age of the BMM differentially influences the proliferation of leukaemic cells and thereby the development and persistence of different types of leukaemias by utilising different in vitro culture experiments. Specifically, we could show that young (compared to old) bone marrow
11 stroma cells (BMSC) support the growth of (BCR-ABL1+) B-ALL cells both in a direct, cell on cell co-culture setting, as well as in young BMSC-derived conditioned medium. This supports the hypothesis that varying factors are differentially released from a young versus an old BMM and influence the growth of the leukaemia cells. The opposite might be true for CML cells (BCR-ABL1+ 32D cells); BMSC obtained from old animals showed a tendency to support their growth more profoundly than cells acquired from young animals.
Possible proteins responsible for the distinct regulation of myeloid versus lymphatic leukaemic cells by young versus old BMM have also been studied. We investigated C-X-C motif chemokine 13 (CXCL13) and growth differentiation factor 11 (GDF11) in their effect on leukaemia cells, as both proteins having previously been described to have tumour-modelling properties and age-dependent levels (see below).
We identified an increased secretion of CXCL13, a B-cell chemotactic factor, into conditioned medium from young versus old BMSC. In accordance with this we found migration of B-ALL cells towards BMSC from young compared to old mice to be improved, while adhesion of both B-ALL and CML cells to young versus old BMSC did not show any differences. By blocking CXCL13 the proliferation-supporting effect of young BMSC on B-ALL cells could be diminished. Similar effects could be demonstrated by blocking GDF11.
In the case of CML cells we could observe the opposite effect; blocking CXCL13 and GDF11 increased their proliferation in a co-culture with BMSC. This supported our hypothesis that both cytokines differentially regulate B-ALL and CML behaviour. After the completion of this thesis, another member of the host-laboratory convincingly demonstrated the role of BMM age in the regulation of B-ALL via CXCL13 signalling (see discussion).
The aim of this thesis is to provide a complete and consistent derivation of second-order dissipative relativistic spin hydrodynamics from quantum field theory. We will proceed in two main steps. The first one is the formulation of spin kinetic theory from quantum field theory using the Wigner-function formalism and performing an expansion in powers of the Planck constant. The essential ingredient here is the nonlocal collision term. We will find that the nonlocality of the collision term arises at first order in the Planck constant and is responsible for the spin alignment with vorticity, as it allows for conversion between spin and orbital angular momentum.
In the second step, this kinetic theory is used as the starting point to derive hydrodynamics including spin degrees of freedom. The so-called canonical form of the conserved currents follows from Noether’s theorem.
Applying an HW pseudo-gauge transformation, we obtain a spin tensor and energy-momentum tensor with obvious physical interpretation. Promoting all components of the HW tensors to be dynamical, we derive
second-order dissipative spin hydrodynamics. The additional equations of motion for the dissipative currents are obtained from kinetic theory generalizing the method of moments to include spin degrees of freedom.
The transverse mass spectra of J/ψ and ψ′ mesons and Ω hyperons produced in central Au+Au collisions at RHIC energies are discussed within a statistical model used successfully for the interpretation of the SPS results. The comparison of the presented model with the future RHIC data should serve as a further crucial test of the hypothesis of statistical production of charmonia at hadronization. Finally, in case of validity, the approach should allow to estimate the mean transverse flow velocity at the quark–gluon plasma hadronization.
Objective In rheumatoid arthritis (RA), chronic inflammation can enhance the development of sarcopenia with a depletion of muscle mass, strength and performance. Currently, a consensus definition for sarcopenia and solid results for the prevalence of sarcopenia in patients with RA are lacking.
Methods In this cross-sectional study, 289 patients ≥18 years with RA were recruited. Dual X-ray absorptiometry was performed to measure appendicular lean mass. Assessment of muscle function included grip strength, gait speed and chair rise time. Prevalence of sarcopenia was defined using the updated European Working Group on Sarcopenia in Older People (EWGSOP2) and the Foundation for the National Institutes of Health (FNIH) definition. In addition, the RA study population was compared with existing data of healthy controls (n=280).
Results 4.5% of patients (59.4±11.3 years) and 0.4% of controls (62.9±11.9 years) were affected by sarcopenia according to the EWGSOP2 definition. Body weight (OR 0.92, 95% CI 0.86 to 0.97), body mass index (BMI) (OR 0.70, 95% CI 0.57 to 0.87), C reactive protein (CRP) (OR 1.05, 95% CI 1.01 to 1.10), disease duration (OR 1.08, 95% CI 1.02 to 1.36), current medication with glucocorticoids (OR 5.25, 95% CI 2.14 to 24.18), cumulative dose of prednisone equivalent (OR 1.04, 95% CI 1.02 to 1.05) and Health Assessment Questionnaire (HAQ) (OR 2.50, 95% CI 1.27 to 4.86) were associated with sarcopenia in patients with RA. In contrast, the prevalence was 2.8% in patients compared with 0.7% in controls when applying the FNIH definition, and body height (OR 0.75, 95% CI 0.64 to 0.88), BMI (OR 1.20, 95% CI 1.02 to 1.41), CRP (OR 1.06, 95% CI 1.01 to 1.11) and HAQ (OR 2.77, 95% CI 1.17 to 6.59) were associated with sarcopenia.
Conclusion Sarcopenia is significantly more common in patients with RA compared with controls using the EWGSOP2 criteria. The FNIH definition revealed sarcopenia in individuals with high BMI and fat mass, regardless of the presence of RA.
Trial registration number It was registered at the German Clinical Trials Registry (DRKS) as well as WHO Clinical Trials Registry (ICTRP) (DRKS00011873, registered on 16 March 2017).
The pion multiplicity per participating nucleon in central nucleus-nucleus collisions at the energies 2-15 A GeV is significantly smaller than in nucleon-nucleon interactions at the same collision energy. This effect of pion suppression is argued to appear due to the evolution of the system produced at the early stage of heavy-ion collisions towards a local thermodynamic equilibrium and further isentropic expansion.
Rapidity distributions of net hyperons (Λ−Λ¯¯¯¯) are compared to distributions of participant protons (p−p¯¯¯). Strangeness production (mean multiplicities of produced Λ/Σ0 hyperons and ⟨K+K¯¯¯¯¯⟩) in central nucleus-nucleus collisions is shown for different collision systems at different energies. An enhanced production of Λ¯¯¯¯ compared to p¯¯¯ is observed at 200 GeV per nucleon.
The NA35 experiment used several independent methods to determine the strange particle production in p+S and S+A collisions. The different techniques show consistent results. Strangeness conservation in full phase space is used as an additional check of the consistency of the data.
On the base of the analysis in full phase space it could be shown that strangeness conservation is fullfilled. The NA35 K0S in S+S and S+Ag are consistent with the NA44 results for K+ and K−. The results of the NA36 collaboration for S+Pb collisions were extrapolated to full phase space. The comparison with the NA35 results shows more than two times lower yields. The ratio of Λ to Λ¯¯¯¯ at midrapidity of NA36 is inconsistent with the high baryon density determind by NA35. The strange particle production is compared to the abundance of non strange particles, especially negatively charged pions which are measured in full phase space in the same experiment. A clear enhanced strange hadron production relative to π− is observed in S+Ag collisions compared to p+S reactions at the same energy. The K0S multiplicity in full phase space per negative hadron (h−) in S+S, S+Ag and Pb+Pb is enhanced by about a factor 1.6 compared to N+N and p+S collisions. The NA36 result for the K0S multiplicity per h− in S+Pb is below the N+N value.
We report a measurement of the observed cross sections of e+ e− → J/ψX based on 3.21 fb − 1 of data accumulated at energies from 3.645 to 3.891 GeV with the BESIII detector operated at the BEPCII collider. In analysis of the cross sections, we measured the decay branching fractions of B(ψ(3686) → J/ψX) = (64.4 ± 0.6 ± 1.6)% and B(ψ(3770) → J/ψX) = (0.5 ± 0.2 ± 0.1)% for the first time. The energy-dependent line shape of these cross sections cannot be well described by two Breit-Wigner (BW) amplitudes of the expected decays ψ (3686) → J/ψX and ψ(3770) → J/ψX. Instead, it can be better described with one more BW amplitude of the decay R(3760)→ J/ψX. Under this assumption, we extracted the R (3760) mass M R (3760 ) = 3766.2 ± 3.8 ± 0.4 MeV/c2, total width Γ tot R ( 3760 ) = 22.2 ± 5.9 ± 1.4 MeV, and product of leptonic width and decay branching fraction
ΓeeR(3760) B[R(3760) → J/ψX] = (79.4 ± 85.5 ± 11.7) eV. The significance of the R(3760) is 5.3σ. The first uncertainties of these measured quantities are from fits to the cross sections and second systematic.
By analyzing 6.32 fb − 1 of e+ e− annihilation data collected at the center-of-mass energies between 4.178 and 4.226 GeV with the BESIII detector, we determine the branching fraction of the leptonic decay D + s → τ + ντ, with τ+ → π + π0¯ντ, to be B D + s → τ + ν τ = (5.29 ± 0.25 stat ± 0.20 syst) %. We estimate the product of the Cabibbo-Kobayashi-Maskawa matrix element |Vcs|and the D + s decay constant f D + s to be f D + s|Vcs| = (244.8 ± 5.8 stat ± 4.8syst) MeV, using the known values of the τ + and D + s masses as well as the D + s lifetime, together with our branching fraction measurement. Combining the value of |Vcs| obtained from a global fit in the standard model and f D + s from lattice quantum chromodynamics, we obtain f D + s = (251.6 ± 5.9 stat ± 4.9syst) MeV and |Vcs| = 0.980 ± 0.023 stat ± 0.019 syst. Using the branching fraction of B D + s → μ + νμ = (5.35±0.21)×10−3, we obtain the ratio of the branching fractions B D + s → τ + ντ/B D +s → μ+νμ = 9.89±0.71, which is consistent with the standard model prediction of lepton flavor universality.
Leukemia is a cancer of the blood and bone marrow characterized by an uncontrolled proliferation and accumulation of abnormal white blood cells. Leukemia can be classified based on the course of the disease (acute or chronic) and the blood cell type involved (myeloid or lymphocytic), leading to four main subtypes: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML). Leukemia represents 2.5% of all new cancer cases per year, and survival rates in some leukemias remain low at 40%.
The bone marrow microenvironment (BMM) is a system within the bone marrow comprising cellular and acellular components, all of which play a major role in hematopoiesis, providing the physical space where hematopoietic stem cells (HSCs) reside. The BMM interacts with HSCs, offering a “niche” for those cells and in case of leukemia, the BMM has a supportive role in disease maintenance and progression by supporting Leukemia stem cells (LSCs). One of the components of the BMM are calcium ions. Calcium is the most abundant mineral in the body, a key component of bones and is released by parathyroid hormone (PTH) induced bone remodeling. Calcium ions play a role in the localization, engraftment and adhesion of normal HSC to extracellular matrix (ECM) proteins in the BMM via the calcium sensing receptor (CaSR), thereby maintaining normal hematopoiesis. In addition of a major regulator of calcium homeostasis, CaSR contribute to the development of different cancers, functioning as either tumor suppressor or oncogene, depending on the involved tissue. However, the role of CaSR and its associated pathways in the local BMM for the development of leukemia is poorly understood. We hypothesized that calcium ions released from bone, subject to a fine balance between osteoblasts and osteoclasts, and/or CaSR, contribute to development, progression and response to therapy.
We have shown that the local calcium concentration forms a gradient in the bone marrow niche and in mice with CML is similarly low as in control mice, but significantly higher in mice suffering from BCR ABL1 driven B ALL or MLL AF9 driven AML. Similarly, the calcium concentration in the human BMM was found to be higher in AML than in other leukemias. Regarding the function of calcium in leukemia cells, we found that AML and CML cells respond differently to calcium exposure, with AML cells exhibiting regulation of cellular processes such as adhesion to the ECM protein fibronectin and migration toward CXCL 12, whereas CML cells remained mostly unaltered. Using genetic deletion or overexpression of CaSR in murine models of leukemia, we observed that CaSR acts as tumor suppressor in BCR-ABL1 driven CML and B ALL and as oncogene in AML.
Focusing on AML, our data shows that deficiency of CaSR on LICs leads, on one hand to increased apoptosis, and on the other hand to reduced cell cycle, reactive oxygen species (ROS) production and DNA damage in vivo, which may explain the observed prolongation of survival of mice. Complementary, in vitro experiments demonstrated that cells overexpressing CaSR have a distinct, cancer promoting phenotype compared to wildtype cells. Overexpression of CaSR led to an increase in proliferation, cell cycle, ROS production, DNA damage and reduced apoptosis. We have identified CaSR mediated pathways in AML and shown that CaSR enhances leukemia progression by activating MAPK/ERK and Wnt β catenin signaling. In addition, the CaSR interacting protein filamin A (FLNA) was shown to contribute to aggressive disease in vitro and in vivo. Furthermore, the mechanism underlying the role of CaSR in AML pathogenesis and possible regulation of LSCs was studied. Our findings demonstrated that CaSR ablation reduces myeloid progenitor function and proved that CaSR is required for maintenance of LSC pool by regulating its frequency and function. Further supporting the role of CaSR in LSC maintenance, genes associated with AML stemness and self renewal capacity were upregulated when CaSR was overexpressed and downregulated when CaSR was depleted. Given the role of CaSR in AML, the CaSR antagonist NPS 2143 was tested in vivo. The combination treatment of NPS 2143 with the standard of care, ara C, significantly reduced the tumor burden and prolonged the survival of mice with AML in syngeneic and xenotransplantation experiments. Based on the finding that CaSR functions as a tumor suppressor in CML, treatment of mice with the CaSR agonist cinacalcet in combination with imatinib prolonged survival of mice with CML compared to treatment with the mice given vehicle.
Our results suggest that calcium ions stemming from the calcium-rich BMM via CaSR strongly and differentially influence leukemia progression. As an adjunct to existing treatment therapies, targeting of CaSR with specific pharmacologic antagonists may prolong survival of patients with AML.
Measurements of the π±, K±, and proton double differential yields emitted from the surface of the 90-cm-long carbon target (T2K replica) were performed for the incoming 31 GeV/c protons with the NA61/SHINE spectrometer at the CERN SPS using data collected during 2010 run. The double differential π± yields were measured with increased precision compared to the previously published NA61/SHINE results, while the K± and proton yields were obtained for the first time. A strategy for dealing with the dependence of the results on the incoming proton beam profile is proposed. The purpose of these measurements is to reduce significantly the (anti)neutrino flux uncertainty in the T2K long-baseline neutrino experiment by constraining the production of (anti)neutrino ancestors coming from the T2K target.
his Erratum replaces incorrect plots shown in Fig. 7 with the corrected ones. In the publication, the NA57 [1] ratios of Ξ− and Ξ¯¯¯¯+ to the number of wounded nucleons at ⟨NW⟩=349 by mistake were plotted at the wrong values. The ratios were calculated and plotted by mistake using ⟨NW⟩=249.
The correct normalization does not change the conclusions of the paper. The correctly normalized results are presented in Fig. 7.
The physics goal of the strong interaction program of the NA61/SHINE experiment at the CERN Super Proton Synchrotron (SPS) is to study the phase diagram of hadronic matter by a scan of particle production in collisions of nuclei with various sizes at a set of energies covering the SPS energy range. This paper presents differential inclusive spectra of transverse momentum, transverse mass and rapidity of π− mesons produced in central 40Ar+45Sc collisions at beam momenta of 13A, 19A, 30A, 40A, 75A and 150A Ge V /c. Energy and system size dependence of parameters of these distributions – mean transverse mass, the inverse slope parameter of transverse mass spectra, width of the rapidity distribution and mean multiplicity – are presented and discussed. Furthermore, the dependence of the ratio of the mean number of produced pions to the mean number of wounded nucleons on the collision energy was derived. The results are compared to predictions of several models.
The cumulant ratios up to fourth order of the Z distributions of the largest fragment in spectator fragmentation following 107,124Sn+Sn and 124La+Sn collisions at 600 MeV/nucleon have been investigated. They are found to exhibit the signatures of a second-order phase transition established with cubic bond percolation and previously observed in the ALADIN experimental data for fragmentation of 197Au projectiles at similar energies. The deduced pseudocritical points are found to be only weakly dependent on the A/Z ratio of the fragmenting spectator source. The same holds for the corresponding chemical freeze-out temperatures of close to 6 MeV.The experimental cumulant distributions are quantitatively reproduced with the Statistical Multifragmentation Model and parameters used to describe the experimental fragment multiplicities, isotope distributions and their correlations with impact-parameter related observables in these reactions. The characteristic coincidence of the zero transition of the skewness with the minimum of the kurtosis excess appears to be a generic property of statistical models and is found to coincide with the maximum of the heat capacity in the canonical thermodynamic fragmentation model.
We study odd parity J=1/2 and J=3/2 Ξc resonances using a unitarized coupled-channel framework based on a SU(6)lsf×HQSS-extended Weinberg–Tomozawa baryon–meson interaction, while paying a special attention to the renormalization procedure. We predict a large molecular ΛcK¯ component for the Ξc(2790) with a dominant 0− light-degree-of-freedom spin configuration. We discuss the differences between the 3/2− Λc(2625) and Ξc(2815) states, and conclude that they cannot be SU(3) siblings, whereas we predict the existence of other Ξc-states, one of them related to the two-pole structure of the Λc(2595). It is of particular interest a pair of J=1/2 and J=3/2 poles, which form a HQSS doublet and that we tentatively assign to the Ξc(2930) and Ξc(2970), respectively. Within this picture, the Ξc(2930) would be part of a SU(3) sextet, containing either the Ωc(3090) or the Ωc(3119), and that would be completed by the Σc(2800). Moreover, we identify a J=1/2 sextet with the Ξb(6227) state and the recently discovered Σb(6097). Assuming the equal spacing rule and to complete this multiplet, we predict the existence of a J=1/2 Ωb odd parity state, with a mass of 6360 MeV and that should be seen in the ΞbK¯ channel.
We investigate the QCD phase diagram for nonzero background magnetic fields using first-principles lattice simulations. At the physical point (in terms of quark masses), the thermodynamics of this system is controlled by two opposing effects: magnetic catalysis (enhancement of the quark condensate) at low temperature and inverse magnetic catalysis (reduction of the condensate) in the transition region. While the former is known to be robust and independent of the details of the interactions, inverse catalysis arises as a result of a delicate competition, effective only for light quarks. By performing simulations at different quark masses, we determine the pion mass above which inverse catalysis does not take place in the transition region anymore. Even for pions heavier than this limiting value — where the quark condensate undergoes magnetic catalysis — our results are consistent with the notion that the transition temperature is reduced by the magnetic field. These findings will be useful to guide low-energy models and effective theories of QCD.
The coordinate and momentum space configurations of the net baryon number in heavy ion collisions that undergo spinodal decomposition, due to a first-order phase transition, are investigated using state-of-the-art machine-learning methods. Coordinate space clumping, which appears in the spinodal decomposition, leaves strong characteristic imprints on the spatial net density distribution in nearly every event which can be detected by modern machine learning techniques. On the other hand, the corresponding features in the momentum distributions cannot clearly be detected, by the same machine learning methods, in individual events. Only a small subset of events can be systematically differ- entiated if only the momentum space information is available. This is due to the strong similarity of the two event classes, with and without spinodal decomposition. In such sce- narios, conventional event-averaged observables like the baryon number cumulants signal a spinodal non-equilibrium phase transition. Indeed the third-order cumulant, the skewness, does exhibit a peak at the beam energy (Elab = 3–4 A GeV), where the transient hot and dense system created in the heavy ion collision reaches the first-order phase transition.
The SU(3) spin model with chemical potential corresponds to a simplified version of QCD with static quarks in the strong coupling regime. It has been studied previously as a testing ground for new methods aiming to overcome the sign problem of lattice QCD. In this work we show that the equation of state and the phase structure of the model can be fully determined to reasonable accuracy by a linked cluster expansion. In particular, we compute the free energy to 14-th order in the nearest neighbour coupling. The resulting predictions for the equation of state and the location of the critical end points agree with numerical determinations to O(1%) and O(10%), respectively. While the accuracy for the critical couplings is still limited at the current series depth, the approach is equally applicable at zero and non-zero imaginary or real chemical potential, as well as to effective QCD Hamiltonians obtained by strong coupling and hopping expansions.
The production of the Λ(1520) baryonic resonance has been measured at midrapidity in inelastic pp collisions at s√=7 TeV and in p–Pb collisions at sNN−−−√=5.02 TeV for non-single diffractive events and in multiplicity classes. The resonance is reconstructed through its hadronic decay channel Λ(1520) →pK− and the charge conjugate with the ALICE detector. The integrated yields and mean transverse momenta are calculated from the measured transverse momentum distributions in pp and p–Pb collisions. The mean transverse momenta follow mass ordering as previously observed for other hyperons in the same collision systems. A Blast-Wave function constrained by other light hadrons (π, K, K0S, p, Λ) describes the shape of the Λ(1520) transverse momentum distribution up to 3.5 GeV/c in p–Pb collisions. In the framework of this model, this observation suggests that the Λ(1520) resonance participates in the same collective radial flow as other light hadrons. The ratio of the yield of Λ(1520) to the yield of the ground state particle Λ remains constant as a function of charged-particle multiplicity, suggesting that there is no net effect of the hadronic phase in p–Pb collisions on the Λ(1520) yield.
Using recent lattice data on the thermodynamics of QCD in the presence of a background magnetic field, we show that the ratio of transverse to longitudinal pressure exhibits, to good accuracy, a simple scaling behavior over a wide range of temperature and magnetic field, essentially depending only on the ratio T/B $$ T/\sqrt{B} $$. We compare this QCD response to the corresponding magnetoresponse in maximally supersymmetric Yang Mills theory. Given suitable calibrations defining the comparison, we find excellent agreement. This may be viewed as a further test of the applicability of holographic models for hot QCD.
We present the charged-particle multiplicity distributions over a wide pseudorapidity range (−3.4<η<5.0) for pp collisions at s√=0.9,7, and 8 TeV at the LHC. Results are based on information from the Silicon Pixel Detector and the Forward Multiplicity Detector of ALICE, extending the pseudorapidity coverage of the earlier publications and the high-multiplicity reach. The measurements are compared to results from the CMS experiment and to PYTHIA, PHOJET and EPOS LHC event generators, as well as IP-Glasma calculations.
Omicron is the evolutionarily most distinct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant of concern (VOC) to date. We report that Omicron BA.1 breakthrough infection in BNT162b2-vaccinated individuals resulted in strong neutralizing activity against Omicron BA.1, BA.2, and previous SARS-CoV-2 VOCs but not against the Omicron sublineages BA.4 and BA.5. BA.1 breakthrough infection induced a robust recall response, primarily expanding memory B (BMEM) cells against epitopes shared broadly among variants, rather than inducing BA.1-specific B cells. The vaccination-imprinted BMEM cell pool had sufficient plasticity to be remodeled by heterologous SARS-CoV-2 spike glycoprotein exposure. Whereas selective amplification of BMEM cells recognizing shared epitopes allows for effective neutralization of most variants that evade previously established immunity, susceptibility to escape by variants that acquire alterations at hitherto conserved sites may be heightened.
We report measurements of the production of prompt D0, D+, D*+ and D+s mesons in Pb–Pb collisions at the centre-of-mass energy per nucleon-nucleon pair sNN−−−√=5.02 TeV, in the centrality classes 0–10%, 30–50% and 60–80%. The D-meson production yields are measured at mid-rapidity (|y| < 0.5) as a function of transverse momentum (pT). The pT intervals covered in central collisions are: 1 < pT< 50 GeV/c for D0, 2 < pT< 50GeV/c for D+, 3 < pT< 50GeV/c for D*+, and 4 < pT< 16GeV/c for D +s mesons. The nuclear modification factors (RAA) for non-strange D mesons (D0, D+, D*+) show minimum values of about 0.2 for pT = 6–10 GeV/c in the most central collisions and are compatible within uncertainties with those measured at s√NN=2.76 TeV. For D +s mesons, the values of RAA are larger than those of non-strange D mesons, but compatible within uncertainties. In central collisions the average RAA of non-strange D mesons is compatible with that of charged particles for pT> 8 GeV/c, while it is larger at lower pT. The nuclear modification factors for strange and non-strange D mesons are also compared to theoretical models with different implementations of in-medium energy loss.
We report the measured transverse momentum (pT) spectra of primary charged particles from pp, p-Pb and Pb-Pb collisions at a center-of-mass energy sNN−−−√=5.02 TeV in the kinematic range of 0.15 < pT< 50 GeV/c and |η| < 0.8. A significant improvement of systematic uncertainties motivated the reanalysis of data in pp and Pb-Pb collisions at sNN−−−√=2.76 TeV, as well as in p-Pb collisions at sNN−−−√=5.02 TeV, which is also presented. Spectra from Pb-Pb collisions are presented in nine centrality intervals and are compared to a reference spectrum from pp collisions scaled by the number of binary nucleon-nucleon collisions. For central collisions, the pT spectra are suppressed by more than a factor of 7 around 6–7 GeV/c with a significant reduction in suppression towards higher momenta up to 30 GeV/c. The nuclear modification factor RpPb, constructed from the pp and p-Pb spectra measured at the same collision energy, is consistent with unity above 8 GeV/c. While the spectra in both pp and Pb-Pb collisions are substantially harder at sNN−−−√=5.02 TeV compared to 2.76 TeV, the nuclear modification factors show no significant collision energy dependence. The obtained results should provide further constraints on the parton energy loss calculations to determine the transport properties of the hot and dense QCD matter.
Measurement of the production of charm jets tagged with D0 mesons in pp collisions at √s = 7 TeV
(2019)
The production of charm jets in proton-proton collisions at a center-of-mass energy of s√=7 TeV was measured with the ALICE detector at the CERN Large Hadron Collider. The measurement is based on a data sample corresponding to a total integrated luminosity of 6.23 nb−1, collected using a minimum-bias trigger. Charm jets are identified by the presence of a D0 meson among their constituents. The D0 mesons are reconstructed from their hadronic decay D0 →K−π+. The D0-meson tagged jets are reconstructed using tracks of charged particles (track-based jets) with the anti-kT algorithm in the jet transverse momentum range 5<pchT,jet< 30 GeV/c and pseudorapidity |ηjet| < 0.5. The fraction of charged jets containing a D0-meson increases with pchT,jet from 0.042 ± 0.004 (stat) ± 0.006 (syst) to 0.080 ± 0.009 (stat) ± 0.008 (syst). The distribution of D0-meson tagged jets as a function of the jet momentum fraction carried by the D0 meson in the direction of the jet axis (zch∥) is reported for two ranges of jet transverse momenta, 5<pchT,jet< 15 GeV/c and 15<pchT,jet< 30 GeV/c in the intervals 0.2<zch∥∥<1.0 and 0.4<zch∥∥<1.0, respectively. The data are compared with results from Monte Carlo event generators (PYTHIA 6, PYTHIA 8 and Herwig 7) and with a Next-to-Leading-Order perturbative Quantum Chromodynamics calculation, obtained with the POWHEG method and interfaced with PYTHIA 6 for the generation of the parton shower, fragmentation, hadronisation and underlying event.
This article reports measurements characterizing the Underlying Event (UE) associated with hard scatterings at midrapidity (|η| < 0.8) in pp collisions at s√ = 13 TeV. The hard scatterings are identified by the leading particle, the charged particle with the highest transverse momentum (pleadingT) in the event. Charged-particle number-densities and summed transverse-momentum densities are measured in different azimuthal regions defined with respect to the leading particle direction: Toward, Transverse, and Away. The Toward and Away regions contain the fragmentation products of the hard scatterings in addition to the UE contribution, whereas particles in the Transverse region are expected to originate predominantly from the UE. The study is performed as a function of pleadingT with three different pT thresholds for the associated particles, ptrackT > 0.15, 0.5, and 1.0 GeV/c. The charged-particle density in the Transverse region rises steeply for low values of pleadingT and reaches a plateau. The results confirm the trend that the charged-particle density in the Transverse region shows a stronger increase with s√ than the inclusive charged-particle density at midrapidity. The UE activity is increased by approximately 20% when going from 7 TeV to 13 TeV pp collisions. The plateau in the Transverse region (5 <pleadingT< 40 GeV/c) is further characterized by the probability distribution of its charged-particle multiplicity normalized to its average value (relative transverse activity, RT) and the mean transverse momentum as a function of RT. Experimental results are compared to model calculations using PYTHIA 8 and EPOS LHC. The overall agreement between models and data is within 30%. These measurements provide new insights on the interplay between hard scatterings and the associated UE in pp collisions.
Higher harmonic non-linear flow modes of charged hadrons in Pb-Pb collisions at √sNN = 5.02 TeV
(2020)
Anisotropic flow coefficients, vn, non-linear flow mode coefficients, χn,mk, and correlations among different symmetry planes, ρn,mk are measured in Pb-Pb collisions at sNN−−−√ = 5.02 TeV. Results obtained with multi-particle correlations are reported for the transverse momentum interval 0.2 < pT < 5.0 GeV/c within the pseudorapidity interval 0.4 < |η| < 0.8 as a function of collision centrality. The vn coefficients and χn,mk and ρn,mk are presented up to the ninth and seventh harmonic order, respectively. Calculations suggest that the correlations measured in different symmetry planes and the non-linear flow mode coefficients are dependent on the shear and bulk viscosity to entropy ratios of the medium created in heavy-ion collisions. The comparison between these measurements and those at lower energies and calculations from hydrodynamic models places strong constraints on the initial conditions and transport properties of the system.
Coherent photoproduction of ρ⁰ vector mesons in ultra-peripheral Pb-Pb collisions at √sNN = 5.02 TeV
(2020)
Cross sections for the coherent photoproduction of ρ0 vector mesons in ultra-peripheral Pb-Pb collisions at sNN−−−√ = 5.02 TeV are reported. The measurements, which rely on the π+π− decay channel, are presented in three regions of rapidity covering the range |y| < 0.8. For each rapidity interval, cross sections are shown for different nuclear-breakup classes defined according to the presence of neutrons measured in the zero-degree calorimeters. The results are compared with predictions based on different models of nuclear shadowing. Finally, the observation of a coherently produced resonance-like structure with a mass around 1.7 GeV/c2 and a width of about 140 MeV/c2 is reported and compared with similar observations from other experiments.
The pT-differential non-linear flow modes, v4,22, v5,32, v6,33 and v6,222 for π±, K±, K0S , p + p¯¯¯, Λ + Λ¯¯¯¯ and ϕ-meson have been measured for the first time at sNN−−−√ = 5.02 TeV in Pb-Pb collisions with the ALICE detector at the Large Hadron Collider. The results were obtained with a multi-particle technique, correlating the identified hadrons with reference charged particles from a different pseudorapidity region. These non-linear observables probe the contribution from the second and third order initial spatial anisotropy coefficients to higher flow harmonics. All the characteristic features observed in previous pT-differential anisotropic flow measurements for various particle species are also present in the non-linear flow modes, i.e. increase of magnitude with increasing centrality percentile, mass ordering at low pT and particle type grouping in the intermediate pT range. Hydrodynamical calculations (iEBE-VISHNU) that use different initial conditions and values of shear and bulk viscosity to entropy density ratios are confronted with the data at low transverse momenta. These calculations exhibit a better agreement with the anisotropic flow coefficients than the non-linear flow modes. These observations indicate that non-linear flow modes can provide additional discriminatory power in the study of initial conditions as well as new stringent constraints to hydrodynamical calculations.
The production yield of prompt D mesons and their elliptic flow coefficient v2 were measured with the Event-Shape Engineering (ESE) technique applied to mid-central (10–30% and 30–50% centrality classes) Pb-Pb collisions at the centre-of-mass energy per nucleon pair sNN−−−√=5.02 TeV, with the ALICE detector at the LHC. The ESE technique allows the classification of events, belonging to the same centrality, according to the azimuthal anisotropy of soft particle production in the collision. The reported measurements give the opportunity to investigate the dynamics of charm quarks in the Quark-Gluon Plasma and provide information on their participation in the collective expansion of the medium. D mesons were reconstructed via their hadronic decays at mid-rapidity, |η| < 0.8, in the transverse momentum interval 1 < pT < 24 GeV/c. The v2 coefficient is found to be sensitive to the event-shape selection confirming a correlation between the D-meson azimuthal anisotropy and the collective expansion of the bulk matter, while the per-event D-meson yields do not show any significant modification within the current uncertainties.
The inclusive J/ψ elliptic (v2) and triangular (v3) flow coefficients measured at forward rapidity (2.5 < y < 4) and the v2 measured at midrapidity (|y| < 0.9) in Pb-Pb collisions at sNN−−−√ = 5.02 TeV using the ALICE detector at the LHC are reported. The entire Pb-Pb data sample collected during Run 2 is employed, amounting to an integrated luminosity of 750 μb−1 at forward rapidity and 93 μb−1 at midrapidity. The results are obtained using the scalar product method and are reported as a function of transverse momentum pT and collision centrality. At midrapidity, the J/ψ v2 is in agreement with the forward rapidity measurement. The centrality averaged results indicate a positive J/ψ v3 with a significance of more than 5σ at forward rapidity in the pT range 2 < pT < 5 GeV/c. The forward rapidity v2, v3, and v3/v2 results at low and intermediate pT (pT ≲ 8 GeV/c) exhibit a mass hierarchy when compared to pions and D mesons, while converging into a species-independent curve at higher pT. At low and intermediate pT, the results could be interpreted in terms of a later thermalization of charm quarks compared to light quarks, while at high pT, path-length dependent effects seem to dominate. The J/ψ v2 measurements are further compared to a microscopic transport model calculation. Using a simplified extension of the quark scaling approach involving both light and charm quark flow components, it is shown that the D-meson vn measurements can be described based on those for charged pions and J/ψ flow.