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The inclusive production of the ψ(2S) charmonium state was studied as a function of centrality in p-Pb collisions at the nucleon-nucleon center of mass energy sNN−−−√ = 5.02 TeV at the CERN LHC. The measurement was performed with the ALICE detector in the center of mass rapidity ranges −4.46<ycms<−2.96 and 2.03<ycms<3.53, down to zero transverse momentum, by reconstructing the ψ(2S) decay to a muon pair. The ψ(2S) production cross section σψ(2S) is presented as a function of the collision centrality, which is estimated through the energy deposited in forward rapidity calorimeters. The relative strength of nuclear effects on the ψ(2S) and on the corresponding 1S charmonium state J/ψ is then studied by means of the double ratio of cross sections [σψ(2S)/σJ/ψ]pPb/[σψ(2S)/σJ/ψ]pp between p-Pb and pp collisions, and by the values of the nuclear modification factors for the two charmonium states. The results show a large suppression of ψ(2S) production relative to the J/ψ at backward (negative) rapidity, corresponding to the flight direction of the Pb-nucleus, while at forward (positive) rapidity the suppressions of the two states are comparable. Finally, comparisons to results from lower energy experiments and to available theoretical models are presented.
The inclusive production of the ψ(2S) charmonium state was studied as a function of centrality in p-Pb collisions at the nucleon-nucleon center of mass energy sNN−−−√ = 5.02 TeV at the CERN LHC. The measurement was performed with the ALICE detector in the center of mass rapidity ranges −4.46<ycms<−2.96 and 2.03<ycms<3.53, down to zero transverse momentum, by reconstructing the ψ(2S) decay to a muon pair. The ψ(2S) production cross section σψ(2S) is presented as a function of the collision centrality, which is estimated through the energy deposited in forward rapidity calorimeters. The relative strength of nuclear effects on the ψ(2S) and on the corresponding 1S charmonium state J/ψ is then studied by means of the double ratio of cross sections [σψ(2S)/σJ/ψ]pPb/[σψ(2S)/σJ/ψ]pp between p-Pb and pp collisions, and by the values of the nuclear modification factors for the two charmonium states. The results show a large suppression of ψ(2S) production relative to the J/ψ at backward (negative) rapidity, corresponding to the flight direction of the Pb-nucleus, while at forward (positive) rapidity the suppressions of the two states are comparable. Finally, comparisons to results from lower energy experiments and to available theoretical models are presented.
The inclusive production of the ψ(2S) charmonium state was studied as a function of centrality in p-Pb collisions at the nucleon-nucleon center of mass energy sNN−−−√ = 5.02 TeV at the CERN LHC. The measurement was performed with the ALICE detector in the center of mass rapidity ranges −4.46<ycms<−2.96 and 2.03<ycms<3.53, down to zero transverse momentum, by reconstructing the ψ(2S) decay to a muon pair. The ψ(2S) production cross section σψ(2S) is presented as a function of the collision centrality, which is estimated through the energy deposited in forward rapidity calorimeters. The relative strength of nuclear effects on the ψ(2S) and on the corresponding 1S charmonium state J/ψ is then studied by means of the double ratio of cross sections [σψ(2S)/σJ/ψ]pPb/[σψ(2S)/σJ/ψ]pp between p-Pb and pp collisions, and by the values of the nuclear modification factors for the two charmonium states. The results show a large suppression of ψ(2S) production relative to the J/ψ at backward rapidity, corresponding to the flight direction of the Pb-nucleus, while at forward rapidity the suppressions of the two states are comparable. Finally, comparisons to results from lower energy experiments and to available theoretical models are presented.
Measurements of charged jet production as a function of centrality are presented for p-Pb collisions recorded at sNN−−−√=5.02 TeV with the ALICE detector. Centrality classes are determined via the energy deposit in neutron calorimeters at zero degree, close to the beam direction, to minimise dynamical biases of the selection. The corresponding number of participants or binary nucleon-nucleon collisions is determined based on the particle production in the Pb-going rapidity region. Jets have been reconstructed in the central rapidity region from charged particles with the anti-kT algorithm for resolution parameters R=0.2 and R=0.4 in the transverse momentum range 20 to 120 GeV/c. The reconstructed jet momentum and yields have been corrected for detector effects and underlying-event background. In the five centrality bins considered, the charged jet production in p-Pb collisions is consistent with the production expected from binary scaling from pp collisions. The ratio of jet yields reconstructed with the two different resolution parameters is also independent of the centrality selection, demonstrating the absence of major modifications of the radial jet structure in the reported centrality classes.
Measurements of charged jet production as a function of centrality are presented for p-Pb collisions recorded at sNN−−−√=5.02 TeV with the ALICE detector. Centrality classes are determined via the energy deposit in neutron calorimeters at zero degree, close to the beam direction, to minimise dynamical biases of the selection. The corresponding number of participants or binary nucleon-nucleon collisions is determined based on the particle production in the Pb-going rapidity region. Jets have been reconstructed in the central rapidity region from charged particles with the anti-kT algorithm for resolution parameters R=0.2 and R=0.4 in the transverse momentum range 20 to 120 GeV/c. The reconstructed jet momentum and yields have been corrected for detector effects and underlying-event background. In the five centrality bins considered, the charged jet production in p-Pb collisions is consistent with the production expected from binary scaling from pp collisions. The ratio of jet yields reconstructed with the two different resolution parameters is also independent of the centrality selection, demonstrating the absence of major modifications of the radial jet structure in the reported centrality classes.
Measurements of charged jet production as a function of centrality are presented for p-Pb collisions recorded at sNN−−−√=5.02 TeV with the ALICE detector. Centrality classes are determined via the energy deposit in neutron calorimeters at zero degree, close to the beam direction, to minimise dynamical biases of the selection. The corresponding number of participants or binary nucleon-nucleon collisions is determined based on the particle production in the Pb-going rapidity region. Jets have been reconstructed in the central rapidity region from charged particles with the anti-kT algorithm for resolution parameters R=0.2 and R=0.4 in the transverse momentum range 20 to 120 GeV/c. The reconstructed jet momentum and yields have been corrected for detector effects and underlying-event background. In the five centrality bins considered, the charged jet production in p-Pb collisions is consistent with the production expected from binary scaling from pp collisions. The ratio of jet yields reconstructed with the two different resolution parameters is also independent of the centrality selection, demonstrating the absence of major modifications of the radial jet structure in the reported centrality classes.
Correlated event-by-event fluctuations of flow harmonics in Pb–Pb collisions at √sNN = 2.76 TeV
(2016)
We report the measurements of correlations between event-by-event fluctuations of amplitudes of anisotropic flow harmonics in nucleus-nucleus collisions, obtained for the first time using a new analysis method based on multiparticle cumulants in mixed harmonics. This novel method is robust against systematic biases originating from non-flow effects and by construction any dependence on symmetry planes is eliminated. We demonstrate that correlations of flow harmonics exhibit a better sensitivity to medium properties than the individual flow harmonics. The new measurements are performed in Pb-Pb collisions at the centre-of-mass energy per nucleon pair of sNN−−−√=2.76 TeV by the ALICE experiment at the Large Hadron Collider (LHC). The centrality dependence of correlation between event-by-event fluctuations of the elliptic, v2, and quadrangular, v4, flow harmonics, as well as of anti-correlation between v2 and triangular, v3, flow harmonics are presented. The results cover two different regimes of the initial state configurations: geometry-dominated (in mid-central collisions) and fluctuation-dominated (in the most central collisions). Comparisons are made to predictions from MC-Glauber, viscous hydrodynamics, AMPT and HIJING models. Together with the existing measurements of individual flow harmonics the presented results provide further constraints on initial conditions and the transport properties of the system produced in heavy-ion collisions.
Correlated event-by-event fluctuations of flow harmonics in Pb–Pb collisions at √sNN = 2.76 TeV
(2016)
We report the measurements of correlations between event-by-event fluctuations of amplitudes of anisotropic flow harmonics in nucleus-nucleus collisions, obtained for the first time using a new analysis method based on multiparticle cumulants in mixed harmonics. This novel method is robust against systematic biases originating from non-flow effects and by construction any dependence on symmetry planes is eliminated. We demonstrate that correlations of flow harmonics exhibit a better sensitivity to medium properties than the individual flow harmonics. The new measurements are performed in Pb-Pb collisions at the centre-of-mass energy per nucleon pair of sNN−−−√=2.76 TeV by the ALICE experiment at the Large Hadron Collider (LHC). The centrality dependence of correlation between event-by-event fluctuations of the elliptic, v2, and quadrangular, v4, flow harmonics, as well as of anti-correlation between v2 and triangular, v3, flow harmonics are presented. The results cover two different regimes of the initial state configurations: geometry-dominated (in mid-central collisions) and fluctuation-dominated (in the most central collisions). Comparisons are made to predictions from MC-Glauber, viscous hydrodynamics, AMPT and HIJING models. Together with the existing measurements of individual flow harmonics the presented results provide further constraints on initial conditions and the transport properties of the system produced in heavy-ion collisions.
Correlated event-by-event fluctuations of flow harmonics in Pb–Pb collisions at √sNN = 2.76 TeV
(2016)
We report the measurements of correlations between event-by-event fluctuations of amplitudes of anisotropic flow harmonics in nucleus-nucleus collisions, obtained for the first time using a new analysis method based on multiparticle cumulants in mixed harmonics. This novel method is robust against systematic biases originating from non-flow effects and by construction any dependence on symmetry planes is eliminated. We demonstrate that correlations of flow harmonics exhibit a better sensitivity to medium properties than the individual flow harmonics. The new measurements are performed in Pb-Pb collisions at the centre-of-mass energy per nucleon pair of sNN−−−√=2.76 TeV by the ALICE experiment at the Large Hadron Collider (LHC). The centrality dependence of correlation between event-by-event fluctuations of the elliptic, v2, and quadrangular, v4, flow harmonics, as well as of anti-correlation between v2 and triangular, v3, flow harmonics are presented. The results cover two different regimes of the initial state configurations: geometry-dominated (in mid-central collisions) and fluctuation-dominated (in the most central collisions). Comparisons are made to predictions from MC-Glauber, viscous hydrodynamics, AMPT and HIJING models. Together with the existing measurements of individual flow harmonics the presented results provide further constraints on initial conditions and the transport properties of the system produced in heavy-ion collisions.
We present a Bayesian approach to particle identification (PID) within the ALICE experiment. The aim is to more effectively combine the particle identification capabilities of its various detectors. After a brief explanation of the adopted methodology and formalism, the performance of the Bayesian PID approach for charged pions, kaons and protons in the central barrel of ALICE is studied. PID is performed via measurements of specific energy loss (dE/dx) and time-of-flight. PID efficiencies and misidentification probabilities are extracted and compared with Monte Carlo simulations using high-purity samples of identified particles in the decay channels K0S→π−π+, ϕ→K−K+, and Λ→pπ− in p-Pb collisions at sNN−−−√=5.02 TeV. In order to thoroughly assess the validity of the Bayesian approach, this methodology was used to obtain corrected pT spectra of pions, kaons, protons, and D0 mesons in pp collisions at s√=7 TeV. In all cases, the results using Bayesian PID were found to be consistent with previous measurements performed by ALICE using a standard PID approach. For the measurement of D0→K−π+, it was found that a Bayesian PID approach gave a higher signal-to-background ratio and a similar or larger statistical significance when compared with standard PID selections, despite a reduced identification efficiency. Finally, we present an exploratory study of the measurement of Λ+c→pK−π+ in pp collisions at s√=7 TeV, using the Bayesian approach for the identification of its decay products.
Introduction: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting.
Methods: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators.
Results: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm).
Conclusions: Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.
We present a Bayesian approach to particle identification (PID) within the ALICE experiment. The aim is to more effectively combine the particle identification capabilities of its various detectors. After a brief explanation of the adopted methodology and formalism, the performance of the Bayesian PID approach for charged pions, kaons and protons in the central barrel of ALICE is studied. PID is performed via measurements of specific energy loss (dE/dx) and time-of-flight. PID efficiencies and misidentification probabilities are extracted and compared with Monte Carlo simulations using high-purity samples of identified particles in the decay channels K0S→π−π+, ϕ→K−K+, and Λ→pπ− in p-Pb collisions at sNN−−−√=5.02 TeV. In order to thoroughly assess the validity of the Bayesian approach, this methodology was used to obtain corrected pT spectra of pions, kaons, protons, and D0 mesons in pp collisions at s√=7 TeV. In all cases, the results using Bayesian PID were found to be consistent with previous measurements performed by ALICE using a standard PID approach. For the measurement of D0→K−π+, it was found that a Bayesian PID approach gave a higher signal-to-background ratio and a similar or larger statistical significance when compared with standard PID selections, despite a reduced identification efficiency. Finally, we present an exploratory study of the measurement of Λ+c→pK−π+ in pp collisions at s√=7 TeV, using the Bayesian approach for the identification of its decay products.
We report the first results of elliptic (v2), triangular (v3) and quadrangular flow (v4) of charged particles in Pb-Pb collisions at sNN−−−√=5.02 TeV with the ALICE detector at the CERN Large Hadron Collider. The measurements are performed in the central pseudorapidity region |η|<0.8 and for the transverse momentum range 0.2<pT<5 GeV/c. The anisotropic flow is measured using two-particle correlations with a pseudorapidity gap greater than one unit and with the multi-particle cumulant method. Compared to results from Pb-Pb collisions at sNN−−−√=2.76 TeV, the anisotropic flow coefficients v2, v3 and v4 are found to increase by (3.0±0.6)%, (4.3±1.4)% and (10.2±3.8)%, respectively, in the centrality range 0-50%. This increase can be attributed mostly to an increase of the average transverse momentum between the two energies. The measurements are found to be compatible with hydrodynamic model calculations. This comparison provides a unique opportunity to test the validity of the hydrodynamic picture and the power to further discriminate between various possibilities for the temperature dependence of shear viscosity to entropy density ratio of the produced matter in heavy-ion collisions at the highest energies.
We report the first results of elliptic (v2), triangular (v3) and quadrangular flow (v4) of charged particles in Pb-Pb collisions at sNN−−−√=5.02 TeV with the ALICE detector at the CERN Large Hadron Collider. The measurements are performed in the central pseudorapidity region |η|<0.8 and for the transverse momentum range 0.2<pT<5 GeV/c. The anisotropic flow is measured using two-particle correlations with a pseudorapidity gap greater than one unit and with the multi-particle cumulant method. Compared to results from Pb-Pb collisions at sNN−−−√=2.76 TeV, the anisotropic flow coefficients v2, v3 and v4 are found to increase by (3.0±0.6)%, (4.3±1.4)% and (10.2±3.8)%, respectively, in the centrality range 0-50%. This increase can be attributed mostly to an increase of the average transverse momentum between the two energies. The measurements are found to be compatible with hydrodynamic model calculations. This comparison provides a unique opportunity to test the validity of the hydrodynamic picture and the power to further discriminate between various possibilities for the temperature dependence of shear viscosity to entropy density ratio of the produced matter in heavy-ion collisions at the highest energies.
We report the first results of elliptic (v2), triangular (v3) and quadrangular flow (v4) of charged particles in Pb-Pb collisions at sNN−−−√=5.02 TeV with the ALICE detector at the CERN Large Hadron Collider. The measurements are performed in the central pseudorapidity region |η|<0.8 and for the transverse momentum range 0.2<pT<5 GeV/c. The anisotropic flow is measured using two-particle correlations with a pseudorapidity gap greater than one unit and with the multi-particle cumulant method. Compared to results from Pb-Pb collisions at sNN−−−√=2.76 TeV, the anisotropic flow coefficients v2, v3 and v4 are found to increase by (3.0±0.6)%, (4.3±1.4)% and (10.2±3.8)%, respectively, in the centrality range 0-50%. This increase can be attributed mostly to an increase of the average transverse momentum between the two energies. The measurements are found to be compatible with hydrodynamic model calculations. This comparison provides a unique opportunity to test the validity of the hydrodynamic picture and the power to further discriminate between various possibilities for the temperature dependence of shear viscosity to entropy density ratio of the produced matter in heavy-ion collisions at the highest energies.
We present a Bayesian approach to particle identification (PID) within the ALICE experiment. The aim is to more effectively combine the particle identification capabilities of its various detectors. After a brief explanation of the adopted methodology and formalism, the performance of the Bayesian PID approach for charged pions, kaons and protons in the central barrel of ALICE is studied. PID is performed via measurements of specific energy loss (dE/dx) and time-of-flight. PID efficiencies and misidentification probabilities are extracted and compared with Monte Carlo simulations using high-purity samples of identified particles in the decay channels K0S→π−π+, ϕ→K−K+, and Λ→pπ− in p-Pb collisions at sNN−−−√=5.02 TeV. In order to thoroughly assess the validity of the Bayesian approach, this methodology was used to obtain corrected pT spectra of pions, kaons, protons, and D0 mesons in pp collisions at s√=7 TeV. In all cases, the results using Bayesian PID were found to be consistent with previous measurements performed by ALICE using a standard PID approach. For the measurement of D0→K−π+, it was found that a Bayesian PID approach gave a higher signal-to-background ratio and a similar or larger statistical significance when compared with standard PID selections, despite a reduced identification efficiency. Finally, we present an exploratory study of the measurement of Λ+c→pK−π+ in pp collisions at s√=7 TeV, using the Bayesian approach for the identification of its decay products.
We report the transverse energy (ET) measured with ALICE at midrapidity in Pb-Pb collisions at sNN−−−√ = 2.76 TeV as a function of centrality. The transverse energy was measured using identified single particle tracks. The measurement was cross checked using the electromagnetic calorimeters and the transverse momentum distributions of identified particles previously reported by ALICE. The results are compared to theoretical models as well as to results from other experiments. The mean ET per unit pseudorapidity (η), ⟨dET/dη⟩, in 0-5% central collisions is 1737 ± 6(stat.) ± 97(sys.) GeV. We find a similar centrality dependence of the shape of ⟨dET/dη⟩ as a function of the number of participating nucleons to that seen at lower energies. The growth in ⟨dET/dη⟩ at the LHC sNN−−−√ exceeds extrapolations of low energy data. We observe a nearly linear scaling of ⟨dET/dη⟩ with the number of quark participants. With the canonical assumption of a 1 fm/c formation time, we estimate that the energy density in 0-5% central Pb-Pb collisions at sNN−−−√ = 2.76 TeV is 12.3 ± 1.0 GeV/fm3\xspace and that the energy density at the most central 80 fm2 of the collision is at least 21.5 ± 1.7 GeV/fm3. This is roughly 2.3 times that observed in 0-5% central Au-Au collisions at sNN−−−√ = 200 GeV.
We report the transverse energy (ET) measured with ALICE at midrapidity in Pb-Pb collisions at sNN−−−√ = 2.76 TeV as a function of centrality. The transverse energy was measured using identified single particle tracks. The measurement was cross checked using the electromagnetic calorimeters and the transverse momentum distributions of identified particles previously reported by ALICE. The results are compared to theoretical models as well as to results from other experiments. The mean ET per unit pseudorapidity (η), ⟨dET/dη⟩, in 0-5% central collisions is 1737 ± 6(stat.) ± 97(sys.) GeV. We find a similar centrality dependence of the shape of ⟨dET/dη⟩ as a function of the number of participating nucleons to that seen at lower energies. The growth in ⟨dET/dη⟩ at the LHC sNN−−−√ exceeds extrapolations of low energy data. We observe a nearly linear scaling of ⟨dET/dη⟩ with the number of quark participants. With the canonical assumption of a 1 fm/c formation time, we estimate that the energy density in 0-5% central Pb-Pb collisions at sNN−−−√ = 2.76 TeV is 12.3 ± 1.0 GeV/fm3\xspace and that the energy density at the most central 80 fm2 of the collision is at least 21.5 ± 1.7 GeV/fm3. This is roughly 2.3 times that observed in 0-5% central Au-Au collisions at sNN−−−√ = 200 GeV.
We report the transverse energy (ET) measured with ALICE at midrapidity in Pb-Pb collisions at sNN−−−√ = 2.76 TeV as a function of centrality. The transverse energy was measured using identified single particle tracks. The measurement was cross checked using the electromagnetic calorimeters and the transverse momentum distributions of identified particles previously reported by ALICE. The results are compared to theoretical models as well as to results from other experiments. The mean ET per unit pseudorapidity (η), ⟨dET/dη⟩, in 0-5% central collisions is 1737 ± 6(stat.) ± 97(sys.) GeV. We find a similar centrality dependence of the shape of ⟨dET/dη⟩ as a function of the number of participating nucleons to that seen at lower energies. The growth in ⟨dET/dη⟩ at the LHC sNN−−−√ exceeds extrapolations of low energy data. We observe a nearly linear scaling of ⟨dET/dη⟩ with the number of quark participants. With the canonical assumption of a 1 fm/c formation time, we estimate that the energy density in 0-5% central Pb-Pb collisions at sNN−−−√ = 2.76 TeV is 12.3 ± 1.0 GeV/fm3\xspace and that the energy density at the most central 80 fm2 of the collision is at least 21.5 ± 1.7 GeV/fm3. This is roughly 2.3 times that observed in 0-5% central Au-Au collisions at sNN−−−√ = 200 GeV.
Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
Ziele: Das Ziel dieser offiziellen Leitlinie, die von der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe (DGGG) und der Deutschen Krebsgesellschaft (DKG) publiziert und koordiniert wurde, ist es, die Früherkennung, Diagnostik, Therapie und Nachsorge des Mammakarzinoms zu optimieren.
Methoden: Der Aktualisierungsprozess der S3-Leitlinie aus 2012 basierte zum einen auf der Adaptation identifizierter Quellleitlinien und zum anderen auf Evidenzübersichten, die nach Entwicklung von PICO-(Patients/Interventions/Control/Outcome-)Fragen, systematischer Recherche in Literaturdatenbanken sowie Selektion und Bewertung der gefundenen Literatur angefertigt wurden. In den interdisziplinären Arbeitsgruppen wurden auf dieser Grundlage Vorschläge für Empfehlungen und Statements erarbeitet, die im Rahmen von strukturierten Konsensusverfahren modifiziert und graduiert wurden.
Empfehlungen: Der Teil 1 dieser Kurzversion der Leitlinie zeigt Empfehlungen zur Früherkennung, Diagnostik und Nachsorge des Mammakarzinoms: Der Stellenwert des Mammografie-Screenings wird in der aktualisierten Leitlinienversion bestätigt und bildet damit die Grundlage der Früherkennung. Neben den konventionellen Methoden der Karzinomdiagnostik wird die Computertomografie (CT) zum Staging bei höherem Rückfallrisiko empfohlen. Die Nachsorgekonzepte beinhalten Untersuchungsintervalle für die körperliche Untersuchung, Ultraschall und Mammografie, während weiterführende Gerätediagnostik und Tumormarkerbestimmungen bei der metastasierten Erkrankung Anwendung finden.
Purpose: The aim of this official guideline coordinated and published by the German Society for Gynecology and Obstetrics (DGGG) and the German Cancer Society (DKG) was to optimize the screening, diagnosis, therapy and follow-up care of breast cancer.
Methods: The process of updating the S3 guideline dating from 2012 was based on the adaptation of identified source guidelines which were combined with reviews of evidence compiled using PICO (Patients/Interventions/Control/Outcome) questions and the results of a systematic search of literature databases and the selection and evaluation of the identified literature. The interdisciplinary working groups took the identified materials as their starting point to develop recommendations and statements which were modified and graded in a structured consensus procedure.
Recommendations: Part 1 of this short version of the guideline presents recommendations for the screening, diagnosis and follow-up care of breast cancer. The importance of mammography for screening is confirmed in this updated version of the guideline and forms the basis for all screening. In addition to the conventional methods used to diagnose breast cancer, computed tomography (CT) is recommended for staging in women with a higher risk of recurrence. The follow-up concept includes suggested intervals between physical, ultrasound and mammography examinations, additional high-tech diagnostic procedures, and the determination of tumor markers for the evaluation of metastatic disease.
Methodik
(2002)
Die vegetationskundliche und strukturelle Zuordnung der Lebensraumtypen erfolgt nach der vorrangig von Braun-Blanquet entwickelten Vegetationsklassifizierung, einer hierarchischen Gliederung der Vegetationstypen (Syntaxonomie), die die Ebenen der Assoziation, des Verbandes, der Ordnung und der Klasse umfasst. Hierbei ist die Assoziation die grundlegende Einheit, in der die Pflanzengesellschaften zusammengefasst werden, die sich durch gleiche charakteristische Arten(gruppen)kombinationen auszeichnen. Der Verband vereinigt ähnliche Assoziationen. Das sind bereits umfassendere, jedoch standörtlich noch recht einheitliche Vegetationseinheiten. In Ordnungen werden ähnliche Verbände zusammengefasst. Die Klasse vereinigt ähnliche Ordnungen.
Pseudomonas aeruginosa is a human pathogen that causes health-care associated blood stream infections (BSI). Although P. aeruginosa BSI are associated with high mortality rates, the clinical relevance of pathogen-derived prognostic biomarker to identify patients at risk for unfavorable outcome remains largely unexplored. We found novel pathogen-derived prognostic biomarker candidates by applying a multi-omics approach on a multicenter sepsis patient cohort. Multi-level Cox regression was used to investigate the relation between patient characteristics and pathogen features (2298 accessory genes, 1078 core protein levels, 107 parsimony-informative variations in reported virulence factors) with 30-day mortality. Our analysis revealed that presence of the helP gene encoding a putative DEAD-box helicase was independently associated with a fatal outcome (hazard ratio 2.01, p = 0.05). helP is located within a region related to the pathogenicity island PAPI-1 in close proximity to a pil gene cluster, which has been associated with horizontal gene transfer. Besides helP, elevated protein levels of the bacterial flagellum protein FliL (hazard ratio 3.44, p < 0.001) and of a bacterioferritin-like protein (hazard ratio 1.74, p = 0.003) increased the risk of death, while high protein levels of a putative aminotransferase were associated with an improved outcome (hazard ratio 0.12, p < 0.001). The prognostic potential of biomarker candidates and clinical factors was confirmed with different machine learning approaches using training and hold-out datasets. The helP genotype appeared the most attractive biomarker for clinical risk stratification due to its relevant predictive power and ease of detection.
Aims: Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk.
Methods and results: From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies.
In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95–1.02) in group A, 0.98 (0.93–1.04) in group B, and 0.95 (0.89–1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07–1.23) in group A, 1.13 (1.05–1.22) in group B, and 1.12 (1.05–1.20) in group C.
Conclusions: We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals.
Aims: Averaged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear.
Methods and results: An individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration (n = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events.
Conclusion: Averaged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints.
Fucoxanthin chlorophyll proteins (Fcps), the light-harvesting antennas of heterokont algae, are encoded by a multigene family and are highly similar with respect to their molecular masses as well as to their pigmentation, making it difficult to purify single Fcps. In this study, a hexa-histidine tag was genetically added to the C-terminus of the FcpA protein of the pennate diatom Phaeodactylum tricornutum. A transgenic strain expressing the recombinant His-tagged FcpA protein in addition to the endogenous wild type Fcps was created. This strategy allowed, for the first time, the purification of a specific, stable trimeric Fcp complex. In addition, a pool of various trimeric Fcps was also purified from the wild-type cells using sucrose density gradient ultracentrifugation and gel filtration. In both the His-tagged and the wild-type Fcps, excitation energy coupling between fucoxanthin and chlorophyll a was intact and the existence of a chlorophyll a/fucoxanthin excitonic dimer was demonstrated using circular dichroism spectroscopy. Mass spectrometric analyses of the trimeric His-tagged complex indicated that it is composed of FcpA and FcpE polypeptides. It is confirmed here that a trimer is the basic organizational unit of Fcps in P. tricornutum. From circular dichroism spectra, it is proposed that the organization of the pigments on the polypeptide backbone of Fcps is a conserved feature in the case of chlorophyll a/c containing algae.
Simple Summary: Pseudoprogression detection in glioblastoma patients remains a challenging task. Although pseudoprogression has only a moderate prevalence of 10–30% following first-line treatment of glioblastoma patients, it bears critical implications for affected patients. Non-invasive techniques, such as amino acid PET imaging using the tracer O-(2-[18F]-fluoroethyl)-L-tyrosine (FET), expose features that have been shown to provide useful information to distinguish tumor progression from pseudoprogression. The usefulness of FET-PET in IDH-wildtype glioblastoma exclusively, however, has not been investigated so far. Recently, machine learning (ML) algorithms have been shown to offer great potential particularly when multiparametric data is available. In this preliminary study, a Linear Discriminant Analysis-based ML algorithm was deployed in a cohort of newly diagnosed IDH-wildtype glioblastoma patients (n = 44) and demonstrated a significantly better diagnostic performance than conventional ROC analysis. This preliminary study is the first to assess the performance of ML in FET-PET for diagnosing pseudoprogression exclusively in IDH-wildtype glioblastoma and demonstrates its potential.
Abstract: Pseudoprogression (PSP) detection in glioblastoma remains challenging and has important clinical implications. We investigated the potential of machine learning (ML) in improving the performance of PET using O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) for differentiation of tumor progression from PSP in IDH-wildtype glioblastoma. We retrospectively evaluated the PET data of patients with newly diagnosed IDH-wildtype glioblastoma following chemoradiation. Contrast-enhanced MRI suspected PSP/TP and all patients underwent subsequently an additional dynamic FET-PET scan. The modified Response Assessment in Neuro-Oncology (RANO) criteria served to diagnose PSP. We trained a Linear Discriminant Analysis (LDA)-based classifier using FET-PET derived features on a hold-out validation set. The results of the ML model were compared with a conventional FET-PET analysis using the receiver-operating-characteristic (ROC) curve. Of the 44 patients included in this preliminary study, 14 patients were diagnosed with PSP. The mean (TBRmean) and maximum tumor-to-brain ratios (TBRmax) were significantly higher in the TP group as compared to the PSP group (p = 0.014 and p = 0.033, respectively). The area under the ROC curve (AUC) for TBRmax and TBRmean was 0.68 and 0.74, respectively. Using the LDA-based algorithm, the AUC (0.93) was significantly higher than the AUC for TBRmax. This preliminary study shows that in IDH-wildtype glioblastoma, ML-based PSP detection leads to better diagnostic performance.
Interleukin-7 (IL-7) is an important cytokine with pivotal pro-survival functions in the adaptive immune system. However, the role of IL-7 in innate immunity is not fully understood. In the present study, the impact of hepatic IL-7 on innate immune cells was assessed by functional experiments as well as in patients with different stages of liver cirrhosis or acute-on-chronic liver failure (ACLF). Human hepatocytes and liver sinusoidal endothelial cells secreted IL-7 in response to stimulation with interferons (IFNs) of type I and II, yet not type III. De novo translation of interferon-response factor-1 (IRF-1) restricted IL-7 production to stimulation with type I and II IFNs. LPS-primed human macrophages were identified as innate immune target cells responding to IL-7 signaling by inactivation of Glycogen synthase kinase-3 (GSK3). IL-7-mediated GSK3 inactivation augmented LPS-induced secretion of pro-inflammatory cytokines and blunted LPS tolerance of macrophages. The IFN-IRF-1-IL-7 axis was present in liver cirrhosis patients. However, liver cirrhosis patients with or without ACLF had significantly lower concentrations of IL-7 in serum compared to healthy controls, which might contribute to LPS-tolerance in these patients. In conclusion, we propose the presence of an inflammatory cascade where IFNs of type I/II induce hepatocellular IL-7 in an IRF-1-restriced way. Beyond its role in adaptive immune responses, IL-7 appears to augment the response of macrophages to LPS and to ameliorate LPS tolerance, which may improve innate immune responses against invading pathogens.
Despite the recent availability of vaccines against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), there is an urgent need for specific anti-SARS-CoV-2 drugs. Monoclonal neutralizing antibodies are an important drug class in the global fight against the SARS-CoV-2 pandemic due to their ability to convey immediate protection and their potential to be used as both prophylactic and therapeutic drugs. Clinically used neutralizing antibodies against respiratory viruses are currently injected intravenously, which can lead to suboptimal pulmonary bioavailability and thus to a lower effectiveness. Here we describe DZIF-10c, a fully human monoclonal neutralizing antibody that binds the receptor-binding domain of the SARS-CoV-2 spike protein. DZIF-10c displays an exceptionally high neutralizing potency against SARS-CoV-2, retains full activity against the variant of concern (VOC) B.1.1.7 and still neutralizes the VOC B.1.351, although with reduced potency. Importantly, not only systemic but also intranasal application of DZIF-10c abolished the presence of infectious particles in the lungs of SARS-CoV-2 infected mice and mitigated lung pathology when administered prophylactically. Along with a favorable pharmacokinetic profile, these results highlight DZIF-10c as a novel human SARS-CoV-2 neutralizing antibody with high in vitro and in vivo antiviral potency. The successful intranasal application of DZIF-10c paves the way for clinical trials investigating topical delivery of anti-SARS-CoV-2 antibodies.
How does the need to preserve government debt sustainability affect the optimal monetary and fiscal policy response to a liquidity trap? To provide an answer, we employ a small stochastic New Keynesian model with a zero bound on nominal interest rates and characterize optimal time-consistent stabilization policies. We focus on two policy tools, the short-term nominal interest rate and debt-financed government spending. The optimal policy response to a liquidity trap critically depends on the prevailing debt burden. While the optimal amount of government spending is decreasing in the level of outstanding government debt, future monetary policy is becoming more accommodative, triggering a change in private sector expectations that helps to dampen the fall in output and inflation at the outset of the liquidity trap.
TRPC channels are a family of nonselective cation channels that regulate ion homeostasis and intracellular Ca2+ signaling in numerous cell types. Important physiological functions such as vasoregulation, neuronal growth, and pheromone recognition have been assigned to this class of ion channels. Despite their physiological relevance, few selective pharmacological tools are available to study TRPC channel function. We, therefore, screened a selection of pharmacologically active compounds for TRPC modulating activity. We found that the synthetic gestagen norgestimate inhibited diacylglycerol-sensitive TRPC3 and TRPC6 with IC50s of 3–5 µM, while half-maximal inhibition of TRPC5 required significantly higher compound concentrations (>10 µM). Norgestimate blocked TRPC-mediated vasopressin-induced cation currents in A7r5 smooth muscle cells and caused vasorelaxation of isolated rat aorta, indicating that norgestimate could be an interesting tool for the investigation of TRP channel function in native cells and tissues. The steroid hormone progesterone, which is structurally related to norgestimate, also inhibited TRPC channel activity with IC50s ranging from 6 to 18 µM but showed little subtype selectivity. Thus, TRPC channel inhibition by high gestational levels of progesterone may contribute to the physiological decrease of uterine contractility and immunosuppression during pregnancy.
The illiberal turn in Europe has many facets. Of particular concern are Member States in which ruling majorities uproot the independence of the judiciary. For reasons well described in the Verfassungsblog, the current focus is on Poland. Since the Polish development is emblematic for a broader trend, more is at stake than the rule of law in that Member State alone (as if that were not enough). If the Polish emblematic development is not resisted, illiberal democracies might start co-defining the European constitutional order, in particular, its rule of law-value in Article 2 TEU. Accordingly, the conventional liberal self-understanding of Europe could easily erode, with tremendous implications.
Introduction: Hip fracture surgery is associated with high in-hospital and 30-day mortality rates and serious adverse patient outcomes. Evidence from randomised controlled trials regarding effectiveness of spinal versus general anaesthesia on patient-centred outcomes after hip fracture surgery is sparse.
Methods and analysis: The iHOPE study is a pragmatic national, multicentre, randomised controlled, open-label clinical trial with a two-arm parallel group design. In total, 1032 patients with hip fracture (>65 years) will be randomised in an intended 1:1 allocation ratio to receive spinal anaesthesia (n=516) or general anaesthesia (n=516). Outcome assessment will occur in a blinded manner after hospital discharge and inhospital. The primary endpoint will be assessed by telephone interview and comprises the time to the first occurring event of the binary composite outcome of all-cause mortality or new-onset serious cardiac and pulmonary complications within 30 postoperative days. In-hospital secondary endpoints, assessed via in-person interviews and medical record review, include mortality, perioperative adverse events, delirium, satisfaction, walking independently, length of hospital stay and discharge destination. Telephone interviews will be performed for long-term endpoints (all-cause mortality, independence in walking, chronic pain, ability to return home cognitive function and overall health and disability) at postoperative day 30±3, 180±45 and 365±60.
Ethics and dissemination: iHOPE has been approved by the leading Ethics Committee of the Medical Faculty of the RWTH Aachen University on 14 March 2018 (EK 022/18). Approval from all other involved local Ethical Committees was subsequently requested and obtained. Study started in April 2018 with a total recruitment period of 24 months. iHOPE will be disseminated via presentations at national and international scientific meetings or conferences and publication in peer-reviewed international scientific journals.
Trial registration number: DRKS00013644; Pre-results
Point forecasts can be interpreted as functionals (i.e., point summaries) of predictive distributions. We extend methodology for the identification of the functional based on time series of point forecasts and associated realizations. Focusing on state-dependent quantiles and expectiles, we provide a generalized method of moments estimator for the functional, along with tests of optimality under general joint hypotheses of functional relationships and information bases. Our tests are more flexible, and in simulations better calibrated and more powerful than existing solutions. In empirical examples, economic growth forecasts and model output for precipitation are indicative of overstatement in anticipation of extreme events.
The goal of this report is to prove correctness of a considerable subset of transformations w.r.t. contextual equivalence in an extended lambda-calculus LS with case, constructors, seq, let, and choice, with a simple set of reduction rules; and to argue that an approximation calculus LA is equivalent to LS w.r.t. the contextual preorder, which enables the proof tool of simulation. Unfortunately, a direct proof appears to be impossible.
The correctness proof is by defining another calculus L comprising the complex variants of copy, case-reduction and seq-reductions that use variable-binding chains. This complex calculus has well-behaved diagrams and allows a proof of correctness of transformations, and that the simple calculus LS, the calculus L, and the calculus LA all have an equivalent contextual preorder.
The goal of this report is to prove correctness of a considerable subset of transformations w.r.t. contextual equivalence in an extended lambda-calculus LS with case, constructors, seq, let, and choice, with a simple set of reduction rules; and to argue that an approximation calculus LA is equivalent to LS w.r.t. the contextual preorder, which enables the proof tool of simulation. Unfortunately, a direct proof appears to be impossible.
The correctness proof is by defining another calculus L comprising the complex variants of copy, case-reduction and seq-reductions that use variable-binding chains. This complex calculus has well-behaved diagrams and allows a proof of correctness of transformations, and that the simple calculus LS, the calculus L, and the calculus LA all have an equivalent contextual preorder.
Purpose: The PELICAN trial evaluates for the first time efficacy and safety of pegylated liposomal doxorubicin (PLD) versus capecitabine as first-line treatment of metastatic breast cancer (MBC).
Methods: This randomized, phase III, open-label, multicenter trial enrolled first-line MBC patients who were ineligible for endocrine or trastuzumab therapy. Cumulative adjuvant anthracyclines of 360 mg/m2 doxorubicin or equivalent were allowed. Left ventricular ejection fraction of >50 % was required. Patients received PLD 50 mg/m2 every 28 days or capecitabine 1250 mg/m2 twice daily for 14 days every 21 days. The primary endpoint was time-to-disease progression (TTP).
Results: 210 patients were randomized (n = 105, PLD and n = 105, capecitabine). Adjuvant anthracyclines were given to 37 % (PLD) and 36 % (capecitabine) of patients. No significant difference was observed in TTP [HR = 1.21 (95 % confidence interval, 0.838–1.750)]. Median TTP was 6.0 months for both PLD and capecitabine. Comparing patients with or without prior anthracyclines, no significant difference in TTP was observed in the PLD arm (log-rank P = 0.64). For PLD versus capecitabine, respectively, overall survival (median, 23.3 months vs. 26.8 months) and time-to-treatment failure (median, 4.6 months vs. 3.7 months) were not statistically significantly different. Compared to PLD, patients on capecitabine experienced more serious adverse events (P = 0.015) and more cardiac events among patients who had prior anthracycline exposure (18 vs. 8 %; P = 0.31).
Conclusion: Both PLD and capecitabine are effective first-line agents for MBC.
Brain-derived neurotrophic factor (BDNF), an important neural growth factor, has gained growing interest in neuroscience, but many influencing physiological and analytical aspects still remain unclear. In this study we assessed the impact of storage time at room temperature, repeated freeze/thaw cycles, and storage at −80 °C up to 6 months on serum and ethylenediaminetetraacetic acid (EDTA)-plasma BDNF. Furthermore, we assessed correlations of serum and plasma BDNF concentrations in two independent sets of samples. Coefficients of variations (CVs) for serum BDNF concentrations were significantly lower than CVs of plasma concentrations (n = 245, p = 0.006). Mean serum and plasma concentrations at all analyzed time points remained within the acceptable change limit of the inter-assay precision as declared by the manufacturer. Serum and plasma BDNF concentrations correlated positively in both sets of samples and at all analyzed time points of the stability assessment (r = 0.455 to rs = 0.596; p < 0.004). In summary, when considering the acceptable change limit, BDNF was stable in serum and in EDTA-plasma up to 6 months. Due to a higher reliability, we suggest favoring serum over EDTA-plasma for future experiments assessing peripheral BDNF concentrations.
The goal of this report is to prove correctness of a considerable subset of transformations w.r.t. contextual equivalence in a an extended lambda-calculus with case, constructors, seq, let, and choice, with a simple set of reduction rules. Unfortunately, a direct proof appears to be impossible. The correctness proof is by defining another calculus comprising the complex variants of copy, case-reduction and seq-reductions that use variablebinding chains. This complex calculus has well-behaved diagrams and allows a proof that of correctness of transformations, and also that the simple calculus defines an equivalent contextual order.
Plants, fungi and algae are important components of global biodiversity and are fundamental to all ecosystems. They are the basis for human well-being, providing food, materials and medicines. Specimens of all three groups of organisms are accommodated in herbaria, where they are commonly referred to as botanical specimens.The large number of specimens in herbaria provides an ample, permanent and continuously improving knowledge base on these organisms and an indispensable source for the analysis of the distribution of species in space and time critical for current and future research relating to global biodiversity. In order to make full use of this resource, a research infrastructure has to be built that grants comprehensive and free access to the information in herbaria and botanical collections in general. This can be achieved through digitization of the botanical objects and associated data.The botanical research community can count on a long-standing tradition of collaboration among institutions and individuals. It agreed on data standards and standard services even before the advent of computerization and information networking, an example being the Index Herbariorum as a global registry of herbaria helping towards the unique identification of specimens cited in the literature.In the spirit of this collaborative history, 51 representatives from 30 institutions advocate to start the digitization of botanical collections with the overall wall-to-wall digitization of the flat objects stored in German herbaria. Germany has 70 herbaria holding almost 23 million specimens according to a national survey carried out in 2019. 87% of these specimens are not yet digitized. Experiences from other countries like France, the Netherlands, Finland, the US and Australia show that herbaria can be comprehensively and cost-efficiently digitized in a relatively short time due to established workflows and protocols for the high-throughput digitization of flat objects.Most of the herbaria are part of a university (34), fewer belong to municipal museums (10) or state museums (8), six herbaria belong to institutions also supported by federal funds such as Leibniz institutes, and four belong to non-governmental organizations. A common data infrastructure must therefore integrate different kinds of institutions.Making full use of the data gained by digitization requires the set-up of a digital infrastructure for storage, archiving, content indexing and networking as well as standardized access for the scientific use of digital objects. A standards-based portfolio of technical components has already been developed and successfully tested by the Biodiversity Informatics Community over the last two decades, comprising among others access protocols, collection databases, portals, tools for semantic enrichment and annotation, international networking, storage and archiving in accordance with international standards. This was achieved through the funding by national and international programs and initiatives, which also paved the road for the German contribution to the Global Biodiversity Information Facility (GBIF).Herbaria constitute a large part of the German botanical collections that also comprise living collections in botanical gardens and seed banks, DNA- and tissue samples, specimens preserved in fluids or on microscope slides and more. Once the herbaria are digitized, these resources can be integrated, adding to the value of the overall research infrastructure. The community has agreed on tasks that are shared between the herbaria, as the German GBIF model already successfully demonstrates.We have compiled nine scientific use cases of immediate societal relevance for an integrated infrastructure of botanical collections. They address accelerated biodiversity discovery and research, biomonitoring and conservation planning, biodiversity modelling, the generation of trait information, automated image recognition by artificial intelligence, automated pathogen detection, contextualization by interlinking objects, enabling provenance research, as well as education, outreach and citizen science.We propose to start this initiative now in order to valorize German botanical collections as a vital part of a worldwide biodiversity data pool.
Aim: In the CheckRad-CD8 trial patients with locally advanced head and neck squamous cell cancer are treated with a single cycle of induction chemo-immunotherapy (ICIT). Patients with pathological complete response (pCR) in the re-biopsy enter radioimmunotherapy. Our goal was to study the value of F-18-FDG PET/CT in the prediction of pCR after induction therapy.
Methods: Patients treated within the CheckRad-CD8 trial that additionally received FDG- PET/CT imaging at the following two time points were included: 3–14 days before (pre-ICIT) and 21–28 days after (post-ICIT) receiving ICIT. Tracer uptake in primary tumors (PT) and suspicious cervical lymph nodes (LN +) was measured using different quantitative parameters on EANM Research Ltd (EARL) accredited PET reconstructions. In addition, mean FDG uptake levels in lymphatic and hematopoietic organs were examined. Percent decrease (Δ) in FDG uptake was calculated for all parameters. Biopsy of the PT post-ICIT acquired after FDG-PET/CT served as reference. The cohort was divided in patients with pCR and residual tumor (ReTu).
Results: Thirty-one patients were included. In ROC analysis, ΔSUVmax PT performed best (AUC = 0.89) in predicting pCR (n = 17), with a decline of at least 60% (sensitivity, 0.77; specificity, 0.93). Residual SUVmax PT post-ICIT performed best in predicting ReTu (n = 14), at a cutpoint of 6.0 (AUC = 0.91; sensitivity, 0.86; specificity, 0.88). Combining two quantitative parameters (ΔSUVmax ≥ 50% and SUVmax PT post-ICIT ≤ 6.0) conferred a sensitivity of 0.81 and a specificity of 0.93 for determining pCR. Background activity in lymphatic organs or uptake in suspected cervical lymph node metastases lacked significant predictive value.
Conclusion: FDG-PET/CT can identify patients with pCR after ICIT via residual FDG uptake levels in primary tumors and the related changes compared to baseline. FDG-uptake in LN + had no predictive value.
Trial registry: ClinicalTrials.gov identifier: NCT03426657.
Objective: Combination antiretroviral therapy (cART) has markedly increased survival and quality of life in people living with HIV. With the advent of new treatment options, including single-tablet regimens, durability and efficacy of first-line cART regimens are evolving.
Methods: We analyzed data from the prospective multicenter German Clinical Surveillance of HIV Disease (ClinSurv) cohort of the Robert-Koch Institute. Kaplan–Meier and Cox proportional hazards models were run to examine the factors associated with treatment modification. Recovery after treatment initiation was analyzed comparing pre-cART viral load and CD4+ T-cell counts with follow-up data.
Results: We included 8788 patients who initiated cART between 2005 and 2017. The sample population was predominantly male (n = 7040; 80.1%), of whom 4470 (63.5%) were reporting sex with men as the transmission risk factor. Overall, 4210 (47.9%) patients modified their first-line cART after a median time of 63 months (IQR 59–66). Regimens containing integrase strand transfer inhibitors (INSTI) were associated with significantly lower rates of treatment modification (adjusted hazard ratio 0.44; 95% CI 0.39–0.50) compared to protease inhibitor (PI)-based regimens. We found a decreased durability of first-line cART significantly associated with being female, a low CD4+ T-cell count, cART initiation in the later period (2011–2017), being on a multi-tablet regimen (MTR).
Conclusions: Drug class and MTRs are significantly associated with treatment modification. INSTI-based regimens showed to be superior compared to PI-based regimens in terms of durability.
Correction to: Infection (2020) 48:723–733 https://doi.org/10.1007/s15010-020-01469-6. The original version of this article unfortunately contained a mistake. In this article the authors Dirk Schürmann at affiliation Charité, University Medicine, Berlin, Olaf Degen at affiliation University Clinic Hamburg Eppendorf, Hamburg and Heinz-August Horst at affiliation University Hospital Schleswig–Holstein, Kiel, Germany were missing from the author list. The original article has been corrected.
Carbon-fiber-reinforced plastics are widely used in lightweight marine structures due to their high strength and superior fatigue behavior. In this article, we will present an innovative methodology for simultaneous load and structural monitoring of a carbon-fiber-reinforced plastic rudder stock as part of a big commercial vessel. Experimental results are presented here from a quasi-static tensile test in which the load monitoring is performed using embedded strain sensors. Structural monitoring is based on high-frequency electromechanical impedance spectroscopy combined with dedicated signal processing and surface-mounted piezoelectric transducers. We have achieved the following results: (1) the demonstration of a hybrid monitoring system including load and structural monitoring, (2) successful embedding of strain gauges during composite manufacturing of the carbon-fiber-reinforced plastic rudder stock, (3) development of instrumentation hardware for multichannel electromechanical impedance measurements, and (4) successful damage detection by means of electromechanical impedance spectroscopy in thick carbon-fiber-reinforced plastic rudder stock samples exploiting strain data.
The bile acid activated transcription factor farnesoid X receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic and metabolic disorders. FXR agonists have revealed efficacy in treating non-alcoholic steatohepatitis (NASH), diabetes and dyslipidemia. Here we characterize imatinib as first-in-class allosteric FXR modulator and report the development of an optimized descendant that markedly promotes agonist induced FXR activation in a reporter gene assay and FXR target gene expression in HepG2 cells. Differential effects of imatinib on agonist-induced bile salt export protein and small heterodimer partner expression suggest that allosteric FXR modulation could open a new avenue to gene-selective FXR modulators.
Invasive treatment of NSTEMI patients in German chest pain units – evidence for a treatment paradox
(2018)
Background: Patients with non ST-segment elevation myocardial infarction (NSTEMI) represent the largest fraction of patients with acute coronary syndrome in German Chest Pain units. Recent evidence on early vs. selective percutaneous coronary intervention (PCI) is ambiguous with respect to effects on mortality, myocardial infarction (MI) and recurrent angina. With the present study we sought to investigate the prognostic impact of PCI and its timing in German Chest Pain Unit (CPU) NSTEMI patients.
Methods and results: Data from 1549 patients whose leading diagnosis was NSTEMI were retrieved from the German CPU registry for the interval between 3/2010 and 3/2014. Follow-up was available at median of 167 days after discharge. The patients were grouped into a higher (Group A) and lower risk group (Group B) according to GRACE score and additional criteria on admission. Group A had higher Killip classes, higher BNP levels, reduced EF and significant more triple vessel disease (p < 0.001). Surprisingly, patients in group A less frequently received early diagnostic catheterization and PCI. While conservative management did not affect prognosis in Group B, higher-risk CPU-NSTEMI patients without PCI had a significantly worse survival.
Conclusions: The present results reveal a substantial treatment gap in higher-risk NSTEMI patients in German Chest Pain Units. This treatment paradox may worsen prognosis in patients who could derive the largest benefit from early revascularization.
Extending the method of Howe, we establish a large class of untyped higher-order calculi, in particular such with call-by-need evaluation, where similarity, also called applicative simulation, can be used as a proof tool for showing contextual preorder. The paper also demonstrates that Mann’s approach using an intermediate “approximation” calculus scales up well from a basic call-by-need non-deterministic lambdacalculus to more expressive lambda calculi. I.e., it is demonstrated, that after transferring the contextual preorder of a non-deterministic call-byneed lambda calculus to its corresponding approximation calculus, it is possible to apply Howe’s method to show that similarity is a precongruence. The transfer is not treated in this paper. The paper also proposes an optimization of the similarity-test by cutting off redundant computations. Our results also applies to deterministic or non-deterministic call-by-value lambda-calculi, and improves upon previous work insofar as it is proved that only closed values are required as arguments for similaritytesting instead of all closed expressions.
Understanding how epigenetic variation in non-coding regions is involved in distal gene-expression regulation is an important problem. Regulatory regions can be associated to genes using large-scale datasets of epigenetic and expression data. However, for regions of complex epigenomic signals and enhancers that regulate many genes, it is difficult to understand these associations. We present StitchIt, an approach to dissect epigenetic variation in a gene-specific manner for the detection of regulatory elements (REMs) without relying on peak calls in individual samples. StitchIt segments epigenetic signal tracks over many samples to generate the location and the target genes of a REM simultaneously. We show that this approach leads to a more accurate and refined REM detection compared to standard methods even on heterogeneous datasets, which are challenging to model. Also, StitchIt REMs are highly enriched in experimentally determined chromatin interactions and expression quantitative trait loci. We validated several newly predicted REMs using CRISPR-Cas9 experiments, thereby demonstrating the reliability of StitchIt. StitchIt is able to dissect regulation in superenhancers and predicts thousands of putative REMs that go unnoticed using peak-based approaches suggesting that a large part of the regulome might be uncharted water.
The nucleosynthesis of elements beyond iron is dominated by neutron captures in the s and r processes. However, 32 stable, proton-rich isotopes cannot be formed during those processes, because they are shielded from the s-process flow and r-process β-decay chains. These nuclei are attributed to the p and rp process.
For all those processes, current research in nuclear astrophysics addresses the need for more precise reaction data involving radioactive isotopes. Depending on the particular reaction, direct or inverse kinematics, forward or time-reversed direction are investigated to determine or at least to constrain the desired reaction cross sections.
The Facility for Antiproton and Ion Research (FAIR) will offer unique, unprecedented opportunities to investigate many of the important reactions. The high yield of radioactive isotopes, even far away from the valley of stability, allows the investigation of isotopes involved in processes as exotic as the r or rp processes.
We measured the Coulomb dissociation of 16O into 4He and 12C at the R3B setup in a first campaign within FAIR Phase 0 at GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt. The goal was to improve the accuracy of the experimental data for the 12C(α,γ)16O fusion reaction and to reach lower center-ofmass energies than measured so far.
The experiment required beam intensities of 109 16O ions per second at an energy of 500 MeV/nucleon. The rare case of Coulomb breakup into 12C and 4He posed another challenge: The magnetic rigidities of the particles are so close because of the same mass-to-charge-number ratio A/Z = 2 for 16O, 12C and 4He. Hence, radical changes of the R3B setup were necessary. All detectors had slits to allow the passage of the unreacted 16O ions, while 4He and 12C would hit the detectors' active areas depending on the scattering angle and their relative energies. We developed and built detectors based on organic scintillators to track and identify the reaction products with sufficient precision.