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We report on measurements of a charge-dependent flow using a novel three-particle correlator with ALICE in Pb-Pb collisions at the LHC, and discuss the implications for observation of local parity violation and the Chiral Magnetic Wave (CMW) in heavy-ion collisions. Charge-dependent flow is reported for different collision centralities as a function of the event charge asymmetry. While our results are in qualitative agreement with expectations based on the CMW, the nonzero signal observed in higher harmonics correlations indicates a possible significant background contribution. We also present results on a differential correlator, where the flow of positive and negative charges is reported as a function of the mean charge of the particles and their pseudorapidity separation. We argue that this differential correlator is better suited to distinguish the differences in positive and negative charges expected due to the CMW and the background effects, such as local charge conservation coupled with strong radial and anisotropic flow.
The inclusive J/ψ production has been studied in Pn-Pb and pp collisions at the centre-of-mass energy per nucleon pair sNN−−−√=5.02 TeV, using the ALICE detector at the CERN LHC. The J/ψ meson is reconstructed, in the centre-of-mass rapidity interval 2.5<y<4 and in the transverse-momentum range pT<12 GeV/c, via its decay to a muon pair. In this Letter, we present results on the inclusive J/ψ cross section in pp collisions at s√=5.02 TeV and on the nuclear modification factor RAA. The latter is presented as a function of the centrality of the collision and, for central collisions, as a function of the transverse momentum pT of the J/ψ. The measured RAA values indicate a suppression of the J/ψ in nuclear collisions and are then compared to our previous results obtained in Pb-Pb collisions at sNN−−−√=2.76 TeV. The ratio of the RAA values at the two energies is also computed and compared to calculations of statistical and dynamical models. The numerical value of the ratio for central events (0-10\% centrality) is 1.17±0.04(stat)±0.20(syst). In central events, as a function of pT, a slight increase of RAA with collision energy is visible in the region 2<pT<6 GeV/c. Theoretical calculations provide a good description of the measurements, within uncertainties.
The inclusive J/ψ production has been studied in Pn-Pb and pp collisions at the centre-of-mass energy per nucleon pair sNN−−−√=5.02 TeV, using the ALICE detector at the CERN LHC. The J/ψ meson is reconstructed, in the centre-of-mass rapidity interval 2.5<y<4 and in the transverse-momentum range pT<12 GeV/c, via its decay to a muon pair. In this Letter, we present results on the inclusive J/ψ cross section in pp collisions at s√=5.02 TeV and on the nuclear modification factor RAA. The latter is presented as a function of the centrality of the collision and, for central collisions, as a function of the transverse momentum pT of the J/ψ. The measured RAA values indicate a suppression of the J/ψ in nuclear collisions and are then compared to our previous results obtained in Pb-Pb collisions at sNN−−−√=2.76 TeV. The ratio of the RAA values at the two energies is also computed and compared to calculations of statistical and dynamical models. The numerical value of the ratio for central events (0-10\% centrality) is 1.17±0.04(stat)±0.20(syst). In central events, as a function of pT, a slight increase of RAA with collision energy is visible in the region 2<pT<6 GeV/c. Theoretical calculations provide a good description of the measurements, within uncertainties.
The inclusive J/ψ production has been studied in Pb–Pb and pp collisions at the centre-of-mass energy per nucleon pair √sNN=5.02 TeV, using the ALICE detector at the CERN LHC. The J/ψ meson is reconstructed, in the centre-of-mass rapidity interval 2.5<y<4 and in the transverse-momentum range pT<12 GeV/c, via its decay to a muon pair. In this Letter, we present results on the inclusive J/ψ cross section in pp collisions at √s=5.02 TeV and on the nuclear modification factor RAA. The latter is presented as a function of the centrality of the collision and, for central collisions, as a function of the transverse momentum pT of the J/ψ. The measured RAA values indicate a suppression of the J/ψ in nuclear collisions and are then compared to our previous results obtained in Pb–Pb collisions at √sNN=2.76 TeV. The ratio of the RAA values at the two energies is also computed and compared to calculations of statistical and dynamical models. The numerical value of the ratio for central events (0–10% centrality) is 1.17±0.04(stat)±0.20(syst). In central events, as a function of pT, a slight increase of RAA with collision energy is visible in the region 2<pT<6 GeV/c. Theoretical calculations qualitatively describe the measurements, within uncertainties.
The inclusive charged particle transverse momentum distribution is measured in proton–proton collisions at s=900 GeV at the LHC using the ALICE detector. The measurement is performed in the central pseudorapidity region (|η|<0.8) over the transverse momentum range 0.15<pT<10 GeV/c. The correlation between transverse momentum and particle multiplicity is also studied. Results are presented for inelastic (INEL) and non-single-diffractive (NSD) events. The average transverse momentum for |η|<0.8 is 〈pT〉INEL=0.483±0.001 (stat.)±0.007 (syst.) GeV/c and 〈pT〉NSD=0.489±0.001 (stat.)±0.007 (syst.) GeV/c, respectively. The data exhibit a slightly larger 〈pT〉 than measurements in wider pseudorapidity intervals. The results are compared to simulations with the Monte Carlo event generators PYTHIA and PHOJET.
Background: Eligibility criteria are a critical part of clinical trials, as they define the patient population under investigation. Besides certain patient characteristics, clinical trials often include biomarker testing for eligibility. However, patient-identification mostly relies on the trial site itself and is often a time-consuming procedure, which could result in missing out on potentially eligible patients. Pre-selection of those patients using a registry could facilitate the process of eligibility testing and increase the number of identified patients. One aim with the PRAEGNANT registry (NCT02338167) is to identify patients for therapies based on clinical and molecular data. Here, we report eligibility testing for the SHERBOC trial using the German PRAEGNANT registry.
Methods:Heregulin (HRG) has been reported to identify patients with better responses to therapy with the anti-HER3 monoclonal antibody seribantumab (MM-121). The SHERBOC trial investigated adding seribantumab (MM-121) to standard therapy in patients with advanced HER2-negative, hormone receptor–positive (HR-positive) breast cancer and HRG overexpression. The PRAEGNANT registry was used for identification and tumor testing, helping to link potential HRG positive patients to the trial. Patients enrolled in PRAEGNANT have invasive and metastatic or locally advanced, inoperable breast cancer. Patients eligible for SHERBOC were identified by using the registry. Study aims were to describe the HRG positivity rate, screening procedures, and patient characteristics associated with inclusion and exclusion criteria.
Results: Among 2769 unselected advanced breast cancer patients, 650 were HER2-negative, HR-positive and currently receiving first- or second-line treatment, thus potentially eligible for SHERBOC at the end of current treatment; 125 patients also met further clinical eligibility criteria (e.g. menopausal status, ECOG). In the first/second treatment lines, patients selected for SHERBOC based on further eligibility criteria had a more favorable prognosis than those not selected. HRG status was tested in 38 patients, 14 of whom (36.8%) proved to be HRG-positive.
Conclusion: Using a real-world breast cancer registry allowed identification of potentially eligible patients for SHERBOC focusing on patients with HER3 overexpressing, HR-positive, HER2-negative metastatic breast cancer. This approach may provide insights into differences between patients eligible or non-eligible for clinical trials.
Trial registration: Clinicaltrials, NCT02338167, Registered 14 January 2015 - retrospectively registered.
This study presents comprehensive real-world data on the use of anti-human epidermal growth factor receptor 2 (HER2) therapies in patients with HER2-positive metastatic breast cancer (MBC). Specifically, it describes therapy patterns with trastuzumab (H), pertuzumab + trastuzumab (PH), lapatinib (L), and trastuzumab emtansine (T-DM1). The PRAEGNANT study is a real-time, real-world registry for MBC patients. All therapy lines are documented. This analysis describes the utilization of anti-HER2 therapies as well as therapy sequences. Among 1936 patients in PRAEGNANT, 451 were HER2-positive (23.3%). In the analysis set (417 patients), 53% of whom were included in PRAEGNANT in the first-line setting, 241 were treated with H, 237 with PH, 85 with L, and 125 with T-DM1 during the course of their therapies. The sequence PH → T-DM1 was administered in 51 patients. Higher Eastern Cooperative Oncology Group (ECOG) scores, negative hormone receptor status, and visceral or brain metastases were associated with more frequent use of this therapy sequence. Most patients received T-DM1 after treatment with pertuzumab. Both novel therapies (PH and T-DM1) are utilized in a high proportion of HER2-positive breast cancer patients. As most patients receive T-DM1 after PH, real-world data may help to clarify whether the efficacy of this sequence is similar to that in the approval study.
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.
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.
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.
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.
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.
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.
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.
Ecological networks are more sensitive to plant than to animal extinction under climate change
(2016)
Impacts of climate change on individual species are increasingly well documented, but we lack understanding of how these effects propagate through ecological communities. Here we combine species distribution models with ecological network analyses to test potential impacts of climate change on >700 plant and animal species in pollination and seed-dispersal networks from central Europe. We discover that animal species that interact with a low diversity of plant species have narrow climatic niches and are most vulnerable to climate change. In contrast, biotic specialization of plants is not related to climatic niche breadth and vulnerability. A simulation model incorporating different scenarios of species coextinction and capacities for partner switches shows that projected plant extinctions under climate change are more likely to trigger animal coextinctions than vice versa. This result demonstrates that impacts of climate change on biodiversity can be amplified via extinction cascades from plants to animals in ecological networks.
Background: Intensive Care Resources are heavily utilized during the COVID-19 pandemic. However, risk stratification and prediction of SARS-CoV-2 patient clinical outcomes upon ICU admission remain inadequate. This study aimed to develop a machine learning model, based on retrospective & prospective clinical data, to stratify patient risk and predict ICU survival and outcomes. Methods: A Germany-wide electronic registry was established to pseudonymously collect admission, therapeutic and discharge information of SARS-CoV-2 ICU patients retrospectively and prospectively. Machine learning approaches were evaluated for the accuracy and interpretability of predictions. The Explainable Boosting Machine approach was selected as the most suitable method. Individual, non-linear shape functions for predictive parameters and parameter interactions are reported. Results: 1039 patients were included in the Explainable Boosting Machine model, 596 patients retrospectively collected, and 443 patients prospectively collected. The model for prediction of general ICU outcome was shown to be more reliable to predict “survival”. Age, inflammatory and thrombotic activity, and severity of ARDS at ICU admission were shown to be predictive of ICU survival. Patients’ age, pulmonary dysfunction and transfer from an external institution were predictors for ECMO therapy. The interaction of patient age with D-dimer levels on admission and creatinine levels with SOFA score without GCS were predictors for renal replacement therapy. Conclusions: Using Explainable Boosting Machine analysis, we confirmed and weighed previously reported and identified novel predictors for outcome in critically ill COVID-19 patients. Using this strategy, predictive modeling of COVID-19 ICU patient outcomes can be performed overcoming the limitations of linear regression models. Trial registration “ClinicalTrials” (clinicaltrials.gov) under NCT04455451.
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.
Objectives: The aim of this study was to compare the effects of acupuncture and medical training therapy alone and in combination with those of usual care on the pain sensation of patients with frequent episodic and chronic tension-type headache.
Design: This was a prospective single-centre randomised controlled trial with four balanced treatment arms. The allocation was carried out by pre-generated randomisation lists in the ratio 1:1:1:1 with different permutation block sizes.
Setting: The study was undertaken in the outpatient clinic of Rehabilitation Medicine of the Hannover Medical School.
Participants and interventions: Ninety-six adult patients with tension-type headache were included and randomised into usual care (n = 24), acupuncture (n = 24), medical training (n = 24), and combination of acupuncture and medical training (n = 24). One patient was excluded from analysis because of withdrawing her/his consent, leaving 95 patients for intention to treat analysis. Each therapy arm consisted of 6 weeks of treatment with 12 interventions. Follow-up was at 3 and 6 months.
Main outcome measures: Pain intensity (average, maximum and minimum), frequency of headache, responder rate (50% frequency reduction), duration of headache and use of headache medication.
Clinical results: The combination of acupuncture and medical training therapy significantly reduced mean pain intensity compared to usual care (mean = −38%, standard deviation = 25%, p = 0.012). Comparable reductions were observed for maximal pain intensity (−25%, standard deviation = 20%, 0.014) and for minimal pain intensity (−35%, standard deviation = 31%, 0.03). In contrast, neither acupuncture nor medical training therapy differed significantly from usual care. No between-group differences were found in headache frequency, mean duration of headache episodes, and pain medication intake. At 3 months, the majority of all patients showed a reduction of at least 50% in headache frequency. At 6 months, significantly higher responder rates were found in all intervention groups compared to usual care.
Conclusions: In contrast to monotherapy, only the combination of acupuncture and medical training therapy was significantly superior in reduction of pain intensity compared to usual care.
Propranolol as a potentially novel treatment of arteriovenous malformations: from bench to bedside
(2022)
Background: Propranolol is a non-selective blocker of the β-adrenergic receptor and has been used for treatment of proliferative infantile hemangiomas. The vasoconstrictive and antiangiogenic effects of propranolol led us to explore its potential application for the treatment of AVMs.
Methods: AVM tissue was cultured after surgical resection in the presence of 100μM propranolol or solvent DMSO. After incubation for 72 hours, tissue was harvested for testing. The expression levels of SDF1α, CXCR4, VEGF and HIF-1 was measured by rt-PCR. Furthermore, data of patients in 2 vascular centres harboring AVM was retrospectively interrogated for a time period of 20 years. The database included information about hemorrhage, AVM size and antihypertensive medication. Descriptive analyses were performed, focusing on the risk of hemorrhage, size of the lesion at presentation and clinical follow-up in patients on β-blocker medication versus those who were not.
Results: Among 483 patients, 73 (15%) were under β-blocker-treatment. 48% AVMs presented with hemorrhage at diagnosis. Patients under β-blocker-treatment had a lower risk of hemorrhage at the time of diagnosis in a univariate analysis (p<0,0001;OR13). Patients under β-blocker-treatment showed a significant higher chance for a lower Spetzler-Martin-grade ≤III (p<0,0001;OR6,5) and a lower risk for the presence of an associated aneurysm (p<0,0001;OR3,6).
Multivariate analysis including Spetzler-Martin-Grading, young age ≤50, presence of associated aneurysm and β-blocker-treatment showed reduced risk for hemorrhage under β-blocker-treatment (p<0,01,OR0,2).
The expression of CXCR4 was suppressed by propranolol most likely through the HIF-1-pathways. The gene-expression of vasculogenesis factors was decreased in with propranolol incubated AVMs.
Conclusion: β-Blocker medication seems to be associated with a decreased risk of AVM-related hemorrhage and AVM-size at presentation or during follow-up. Propranolol inhibits SDF1α-induced vasculogenesis by suppressing the expression of CXCR4 most likely through the HIF-1-pathways. Therefore, SDF1α/CXCR4 axis plays an important role in the vasculogenesis and migration of inflammatory cells in AVM lesions.
Insertion of bone substitution materials accelerates healing of osteoporotic fractures. Biodegradable materials are preferred for application in osteoporotic patients to avoid a second surgery for implant replacement. Degraded implant fragments are often absorbed by macrophages that are removed from the fracture side via passage through veins or lymphatic vessels. We investigated if lymphatic vessels occur in osteoporotic bone defects and whether they are regulated by the use of different materials. To address this issue osteoporosis was induced in rats using the classical method of bilateral ovariectomy and additional calcium and vitamin deficient diet. In addition, wedge-shaped defects of 3, 4, or 5 mm were generated in the distal metaphyseal area of femur via osteotomy. The 4 mm defects were subsequently used for implantation studies where bone substitution materials of calcium phosphate cement, composites of collagen and silica, and iron foams with interconnecting pores were inserted. Different materials were partly additionally functionalized by strontium or bisphosphonate whose positive effects in osteoporosis treatment are well known. The lymphatic vessels were identified by immunohistochemistry using an antibody against podoplanin. Podoplanin immunopositive lymphatic vessels were detected in the granulation tissue filling the fracture gap, surrounding the implant and growing into the iron foam through its interconnected pores. Significant more lymphatic capillaries were counted at the implant interface of composite, strontium and bisphosphonate functionalized iron foam. A significant increase was also observed in the number of lymphatics situated in the pores of strontium coated iron foam. In conclusion, our results indicate the occurrence of lymphatic vessels in osteoporotic bone. Our results show that lymphatic vessels are localized at the implant interface and in the fracture gap where they might be involved in the removal of lymphocytes, macrophages, debris and the implants degradation products. Therefore the lymphatic vessels are involved in implant integration and fracture healing.
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.
The adult human body contains about 4 g of iron. About 1–2 mg of iron is absorbed every day, and in healthy individuals, the same amount is excreted. We describe a patient who presents with severe iron deficiency anemia with hemoglobin levels below 6 g/dL and ferritin levels below 30 ng/mL. Although red blood cell concentrates and intravenous iron have been substituted every month for years, body iron stores remain depleted. Diagnostics have included several esophago-gastro-duodenoscopies, colonoscopies, MRI of the liver, repetitive bone marrow biopsies, psychological analysis, application of radioactive iron to determine intact erythropoiesis, and measurement of iron excretion in urine and feces. Typically, gastrointestinal bleeding is a major cause of iron loss. Surprisingly, intestinal iron excretion in stool in the patient was repetitively increased, without gastrointestinal bleeding. Furthermore, whole exome sequencing was performed in the patient and additional family members to identify potential causative genetic variants that may cause intestinal iron loss. Under different inheritance models, several rare mutations were identified, two of which (in CISD1 and KRI1) are likely to be functionally relevant. Intestinal iron loss in the current form has not yet been described and is, with high probability, the cause of the severe iron deficiency anemia in this patient.
Postoperative complications after pancreatic surgery are still a significant problem in clinical practice. The aim of this study was to characterize and compare the microbiomes of different body compartments (bile duct, duodenal mucosa, pancreatic tumor lesion, postoperative drainage fluid, and stool samples; preoperative and postoperative) in patients undergoing pancreatic surgery for suspected pancreatic cancer, and their association with relevant clinical factors (stent placement, pancreatic fistula, and gland texture). For this, solid (duodenal mucosa, pancreatic tumor tissue, stool) and liquid (bile, drainage fluid) biopsy samples of 10 patients were analyzed using 16s rRNA gene next-generation sequencing. Our analysis revealed: (i) a distinct microbiome in the different compartments, (ii) markedly higher abundance of Enterococcus in patients undergoing preoperative stent placement in the common bile duct, (iii) significant differences in the beta diversity between patients who developed a postoperative pancreatic fistula (POPF B/C), (iv) patients with POPF B/C were more likely to have bacteria belonging to the genus Enterococcus, and (v) differences in microbiome composition with regard to the pancreatic gland texture. The structure of the microbiome is distinctive in different compartments, and can be associated with the development of a postoperative pancreatic fistula.
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
Introduction: Vasospastic brain infarction is a devastating complication of aneurysmal subarachnoid hemorrhage (SAH). Using a probe for invasive monitoring of brain tissue oxygenation or blood flow is highly focal and may miss the site of cerebral vasospasm (CVS). Probe placement is based on the assumption that the spasm will occur either at the dependent vessel territory of the parent artery of the ruptured aneurysm or at the artery exposed to the focal thick blood clot. We investigated the likelihood of a focal monitoring sensor being placed in vasospasm or infarction territory on a hypothetical basis.
Methods: From our database we retrospectively selected consecutive SAH patients with angiographically proven (day 7–14) severe CVS (narrowing of vessel lumen >50%). Depending on the aneurysm location we applied a standard protocol of probe placement to detect the most probable site of severe CVS or infarction. We analyzed whether the placement was congruent with existing CVS/infarction.
Results: We analyzed 100 patients after SAH caused by aneurysms located in the following locations: MCA (n = 14), ICA (n = 30), A1CA (n = 4), AcoA or A2CA (n = 33), and VBA (n = 19). Sensor location corresponded with CVS territory in 93% of MCA, 87% of ICA, 76% of AcoA or A2CA, but only 50% of A1CA and 42% of VBA aneurysms. The focal probe was located inside the infarction territory in 95% of ICA, 89% of MCA, 78% of ACoA or A2CA, 50% of A1CA and 23% of VBA aneurysms.
Conclusion: The probability that a single focal probe will be situated in the territory of severe CVS and infarction varies. It seems to be reasonably accurate for MCA and ICA aneurysms, but not for ACA or VBA aneurysms.
Background and purpose: During acute coronavirus disease 2019 (COVID-19) infection, neurological signs, symptoms and complications occur. We aimed to assess their clinical relevance by evaluating real-world data from a multinational registry. Methods: We analyzed COVID-19 patients from 127 centers, diagnosed between January 2020 and February 2021, and registered in the European multinational LEOSS (Lean European Open Survey on SARS-Infected Patients) registry. The effects of prior neurological diseases and the effect of neurological symptoms on outcome were studied using multivariate logistic regression. Results: A total of 6537 COVID-19 patients (97.7% PCR-confirmed) were analyzed, of whom 92.1% were hospitalized and 14.7% died. Commonly, excessive tiredness (28.0%), headache (18.5%), nausea/emesis (16.6%), muscular weakness (17.0%), impaired sense of smell (9.0%) and taste (12.8%), and delirium (6.7%) were reported. In patients with a complicated or critical disease course (53%) the most frequent neurological complications were ischemic stroke (1.0%) and intracerebral bleeding (ICB; 2.2%). ICB peaked in the critical disease phase (5%) and was associated with the administration of anticoagulation and extracorporeal membrane oxygenation (ECMO). Excessive tiredness (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.20–1.68) and prior neurodegenerative diseases (OR 1.32, 95% CI 1.07–1.63) were associated with an increased risk of an unfavorable outcome. Prior cerebrovascular and neuroimmunological diseases were not associated with an unfavorable short-term outcome of COVID-19. Conclusion: Our data on mostly hospitalized COVID-19 patients show that excessive tiredness or prior neurodegenerative disease at first presentation increase the risk of an unfavorable short-term outcome. ICB in critical COVID-19 was associated with therapeutic interventions, such as anticoagulation and ECMO, and thus may be an indirect complication of a life-threatening systemic viral infection.
INTRODUCTION: Older patients with acute myeloid leukemia (AML) experience short survival despite intensive chemotherapy. Azacitidine has promising activity in patients with low proliferating AML. The aim of this dose-finding part of this trial was to evaluate feasibility and safety of azacitidine combined with a cytarabine- and daunorubicin-based chemotherapy in older patients with AML.
TRIAL DESIGN: Prospective, randomised, open, phase II trial with parallel group design and fixed sample size.
PATIENTS AND METHODS: Patients aged 61 years or older, with untreated acute myeloid leukemia with a leukocyte count of <20,000/µl at the time of study entry and adequate organ function were eligible. Patients were randomised to receive azacitidine either 37.5 (dose level 1) or 75 mg/sqm (dose level 2) for five days before each cycle of induction (7+3 cytarabine plus daunorubicine) and consolidation (intermediate-dose cytarabine) therapy. Dose-limiting toxicity was the primary endpoint.
RESULTS: Six patients each were randomised into each dose level and evaluable for analysis. No dose-limiting toxicity occurred in either dose level. Nine serious adverse events occurred in five patients (three in the 37.5 mg, two in the 75 mg arm) with two fatal outcomes. Two patients at the 37.5 mg/sqm dose level and four patients at the 75 mg/sqm level achieved a complete remission after induction therapy. Median overall survival was 266 days and median event-free survival 215 days after a median follow up of 616 days.
CONCLUSIONS: The combination of azacitidine 75 mg/sqm with standard induction therapy is feasible in older patients with AML and was selected as an investigational arm in the randomised controlled part of this phase-II study, which is currently halted due to an increased cardiac toxicity observed in the experimental arm.
Microangiopathy with subsequent organ damage represents a major complication in several diseases. The mechanisms leading to microvascular occlusion include von Willebrand factor (VWF), notably the formation of ultra-large von Willebrand factor fibers (ULVWFs) and platelet aggregation. To date, the contribution of erythrocytes to vascular occlusion is incompletely clarified. We investigated the platelet-independent interaction between stressed erythrocytes and ULVWFs and its consequences for microcirculation and organ function under dynamic conditions. In response to shear stress, erythrocytes interacted strongly with VWF to initiate the formation of ULVWF/erythrocyte aggregates via the binding of Annexin V to the VWF A1 domain. VWF-erythrocyte adhesion was attenuated by heparin and the VWF-specific protease ADAMTS13. In an in vivo model of renal ischemia/reperfusion injury, erythrocytes adhered to capillaries of wild-type but not VWF-deficient mice and later resulted in less renal damage. In vivo imaging in mice confirmed the adhesion of stressed erythrocytes to the vessel wall. Moreover, enhanced eryptosis rates and increased VWF binding were detected in blood samples from patients with chronic renal failure. Our study demonstrates that stressed erythrocytes have a pronounced binding affinity to ULVWFs. The discovered mechanisms suggest that erythrocytes are essential for the pathogenesis of microangiopathies and renal damage by actively binding to ULVWFs.
Hintergrund: Ab Frühjahr 2020 kam es zur weltweiten Verbreitung von SARS-CoV‑2 mit der heute als erste Welle der Pandemie bezeichneten Phase ab März 2020. Diese resultierte an vielen Kliniken in Umstrukturierungen und Ressourcenverschiebungen. Ziel unserer Arbeit war die Erfassung der Auswirkungen der Pandemie auf die universitäre Hals-Nasen-Ohren(HNO)-Heilkunde für die Forschung, Lehre und Weiterbildung. Material und Methoden: Die Direktorinnen und Direktoren der 39 Universitäts-HNO-Kliniken in Deutschland wurden mithilfe einer strukturierten Online-Befragung zu den Auswirkungen der Pandemie im Zeitraum von März bis April 2020 auf die Forschung, Lehre und die Weiterbildung befragt. Ergebnisse: Alle 39 Direktorinnen und Direktoren beteiligten sich an der Umfrage. Hiervon gaben 74,4 % (29/39) an, dass es zu einer Verschlechterung ihrer Forschungstätigkeit infolge der Pandemie gekommen sei. Von 61,5 % (24/39) wurde berichtet, dass pandemiebezogene Forschungsaspekte aufgegriffen wurden. Von allen Kliniken wurde eine Einschränkung der Präsenzlehre berichtet und 97,5 % (38/39) führten neue digitale Lehrformate ein. Im Beobachtungszeitraum sahen 74,4 % der Klinikdirektoren die Weiterbildung der Assistenten nicht gefährdet. Schlussfolgerung: Die Ergebnisse geben einen Einblick in die heterogenen Auswirkungen der Pandemie. Die kurzfristige Bearbeitung pandemiebezogener Forschungsthemen und die Einführung innovativer digitaler Konzepte für die studentische Lehre belegt eindrücklich das große innovative Potenzial und die schnelle Reaktionsfähigkeit der HNO-Universitätskliniken, um auch während der Pandemie ihre Aufgaben in der Forschung, Lehre und Weiterbildung bestmöglich zu erfüllen.
Simple Summary: Renal insufficiency is frequently seen in newly diagnosed multiple myeloma and can be due to the disease itself but also caused by medical interventions or infections. Patients with severe renal insufficiency are known to have an adverse prognosis, but recently, it was shown that even moderately impaired kidney function can have long-term sequelae. Achieving quick disease control by effective antimyeloma therapy can lead to the recovery of renal function. We investigated the kidney-specific variables in a large cohort of 770 myeloma patients receiving three different three-drug regimens for initial myeloma treatment to learn more about the differential effects on kidney function in an early disease phase. All regimens had a positive impact on kidney function without a difference in the proportion of patients who reached normal renal function after three cycles. Interestingly, patients who received bortezomib, lenalidomide, and dexamethasone tended to have higher risk for a worse renal function following induction when compared to the initial values.
Abstract: Background: Preservation of kidney function in newly diagnosed (ND) multiple myeloma (MM) helps to prevent excess toxicity. Patients (pts) from two prospective trials were analyzed, provided postinduction (PInd) restaging was performed. Pts received three cycles with bortezomib (btz), cyclophosphamide, and dexamethasone (dex; VCD) or btz, lenalidomide (len), and dex (VRd) or len, adriamycin, and dex (RAD). The minimum required estimated glomerular filtration rate (eGFR) was >30 mL/min. We analyzed the percent change of the renal function using the International Myeloma Working Group (IMWG) criteria and Kidney Disease: Improving Global Outcomes (KDIGO)-defined categories. Results: Seven hundred and seventy-two patients were eligible. Three hundred and fifty-six received VCD, 214 VRd, and 202 RAD. VCD patients had the best baseline eGFR. The proportion of pts with eGFR <45 mL/min decreased from 7.3% at baseline to 1.9% PInd (p < 0.0001). Thirty-seven point one percent of VCD versus 49% of VRd patients had a decrease of GFR (p = 0.0872). IMWG-defined “renal complete response (CRrenal)” was achieved in 17/25 (68%) pts after VCD, 12/19 (63%) after RAD, and 14/27 (52%) after VRd (p = 0.4747). Conclusions: Analyzing a large and representative newly diagnosed myeloma (NDMM) group, we found no difference in CRrenal that occurred independently from the myeloma response across the three regimens. A trend towards deterioration of the renal function with VRd versus VCD may be explained by a better pretreatment “renal fitness” in the latter group.
Purpose: A study of real-time adaptive radiotherapy systems was performed to test the hypothesis that, across delivery systems and institutions, the dosimetric accuracy is improved with adaptive treatments over non-adaptive radiotherapy in the presence of patient-measured tumor motion.
Methods and materials: Ten institutions with robotic(2), gimbaled(2), MLC(4) or couch tracking(2) used common materials including CT and structure sets, motion traces and planning protocols to create a lung and a prostate plan. For each motion trace, the plan was delivered twice to a moving dosimeter; with and without real-time adaptation. Each measurement was compared to a static measurement and the percentage of failed points for γ-tests recorded.
Results: For all lung traces all measurement sets show improved dose accuracy with a mean 2%/2 mm γ-fail rate of 1.6% with adaptation and 15.2% without adaptation (p < 0.001). For all prostate the mean 2%/2 mm γ-fail rate was 1.4% with adaptation and 17.3% without adaptation (p < 0.001). The difference between the four systems was small with an average 2%/2 mm γ-fail rate of <3% for all systems with adaptation for lung and prostate.
Conclusions: The investigated systems all accounted for realistic tumor motion accurately and performed to a similar high standard, with real-time adaptation significantly outperforming non-adaptive delivery methods.
We report inclusive photon measurements about midrapidity ( |y| <0.5 ) from 197 Au + 197 Au collisions at sqrt[sNN ]=130 GeV at RHIC. Photon pair conversions were reconstructed from electron and positron tracks measured with the Time Projection Chamber (TPC) of the STAR experiment. With this method, an energy resolution of Delta E/E ~ 2% at 0.5 GeV has been achieved. Reconstructed photons have also been used to measure the transverse momentum ( pt ) spectra of pi 0 mesons about midrapidity ( |y| <1 ) via the pi 0 --> gamma gamma decay channel. The fractional contribution of the pi 0 --> gamma gamma decay to the inclusive photon spectrum decreases by 20%±5% between pt =1.65 GeV/c and pt =2.4 GeV/c in the most central events, indicating that relative to pi 0 --> gamma gamma decay the contribution of other photon sources is substantially increasing.
We report on the rapidity and centrality dependence of proton and antiproton transverse mass distributions from 197Au + 197Au collisions at sqrt[sNN ]=130 GeV as measured by the STAR experiment at the Relativistic Heavy Ion Collider (RHIC). Our results are from the rapidity and transverse momentum range of |y| <0.5 and 0.35< pt <1.00 GeV/c . For both protons and antiprotons, transverse mass distributions become more convex from peripheral to central collisions demonstrating characteristics of collective expansion. The measured rapidity distributions and the mean transverse momenta versus rapidity are flat within |y| <0.5 . Comparisons of our data with results from model calculations indicate that in order to obtain a consistent picture of the proton (antiproton) yields and transverse mass distributions the possibility of prehadronic collective expansion may have to be taken into account.
We present the first large-acceptance measurement of event-wise mean transverse momentum <pt> fluctuations for Au-Au collisions at nucleon-nucleon center-of-momentum collision energy sqrt[sNN] = 130 GeV. The observed nonstatistical <pt> fluctuations substantially exceed in magnitude fluctuations expected from the finite number of particles produced in a typical collision. The r.m.s. fractional width excess of the event-wise <pt> distribution is 13.7±0.1(stat) ±1.3(syst)% relative to a statistical reference, for the 15% most-central collisions and for charged hadrons within pseudorapidity range | eta |<1,2 pi azimuth, and 0.15 <= pt <= 2 GeV/c. The width excess varies smoothly but nonmonotonically with collision centrality and does not display rapid changes with centrality which might indicate the presence of critical fluctuations. The reported <pt> fluctuation excess is qualitatively larger than those observed at lower energies and differs markedly from theoretical expectations. Contributions to <pt> fluctuations from semihard parton scattering in the initial state and dissipation in the bulk colored medium are discussed.
We present STAR measurements of the azimuthal anisotropy parameter v2 and the binary-collision scaled centrality ratio RCP for kaons and lambdas ( Lambda + Lambda -bar) at midrapidity in Au+Au collisions at sqrt[sNN]=200 GeV. In combination, the v2 and RCP particle-type dependencies contradict expectations from partonic energy loss followed by standard fragmentation in vacuum. We establish pT ~ 5 GeV/c as the value where the centrality dependent baryon enhancement ends. The K0S and Lambda + Lambda -bar v2 values are consistent with expectations of constituent-quark-number scaling from models of hadron formation by parton coalescence or recombination.
Pion-kaon correlation functions are constructed from central Au+Au STAR data taken at sqrt[sNN]=130 GeV by the STAR detector at the Relativistic Heavy Ion Collider (RHIC). The results suggest that pions and kaons are not emitted at the same average space-time point. Space-momentum correlations, i.e., transverse flow, lead to a space-time emission asymmetry of pions and kaons that is consistent with the data. This result provides new independent evidence that the system created at RHIC undergoes a collective transverse expansion.
Data from the first physics run at the Relativistic Heavy-Ion Collider at Brookhaven National Laboratory, Au+Au collisions at sqrt[sNN]=130 GeV, have been analyzed by the STAR Collaboration using three-pion correlations with charged pions to study whether pions are emitted independently at freeze-out. We have made a high-statistics measurement of the three-pion correlation function and calculated the normalized three-particle correlator to obtain a quantitative measurement of the degree of chaoticity of the pion source. It is found that the degree of chaoticity seems to increase with increasing particle multiplicity.
We report high statistics measurements of inclusive charged hadron production in Au+Au and p+p collisions at sqrt[sNN]=200 GeV. A large, approximately constant hadron suppression is observed in central Au+Au collisions for 5<pT<12 GeV/c. The collision energy dependence of the yields and the centrality and pT dependence of the suppression provide stringent constraints on theoretical models of suppression. Models incorporating initial-state gluon saturation or partonic energy loss in dense matter are largely consistent with observations. We observe no evidence of pT-dependent suppression, which may be expected from models incorporating jet attenuation in cold nuclear matter or scattering of fragmentation hadrons.
The balance function is a new observable based on the principle that charge is locally conserved when particles are pair produced. Balance functions have been measured for charged particle pairs and identified charged pion pairs in Au+Au collisions at sqrt[sNN]=130 GeV at the Relativistic Heavy Ion Collider using STAR. Balance functions for peripheral collisions have widths consistent with model predictions based on a superposition of nucleon-nucleon scattering. Widths in central collisions are smaller, consistent with trends predicted by models incorporating late hadronization.
We present the results of charged particle fluctuations measurements in Au+Au collisions at sqrt[sNN ]=130 GeV using the STAR detector. Dynamical fluctuations measurements are presented for inclusive charged particle multiplicities as well as for identified charged pions, kaons, and protons. The net charge dynamical fluctuations are found to be large and negative providing clear evidence that positive and negative charged particle production is correlated within the pseudorapidity range investigated. Correlations are smaller than expected based on model-dependent predictions for a resonance gas or a quark-gluon gas which undergoes fast hadronization and freeze-out. Qualitative agreement is found with comparable scaled p+p measurements and a heavy ion jet interaction generation model calculation based on independent particle collisions, although a small deviation from the 1/N scaling dependence expected from this model is observed.
We report measurements of single-particle inclusive spectra and two-particle azimuthal distributions of charged hadrons at high transverse momentum (high pT) in minimum bias and central d+Au collisions at sqrt[sNN]=200 GeV. The inclusive yield is enhanced in d+Au collisions relative to binary-scaled p+p collisions, while the two-particle azimuthal distributions are very similar to those observed in p+p collisions. These results demonstrate that the strong suppression of the inclusive yield and back-to-back correlations at high pT previously observed in central Au+Au collisions are due to final-state interactions with the dense medium generated in such collisions.
Azimuthal anisotropy (v2) and two-particle angular correlations of high pT charged hadrons have been measured in Au+Au collisions at sqrt[sNN]=130 GeV for transverse momenta up to 6 GeV/c, where hard processes are expected to contribute significantly. The two-particle angular correlations exhibit elliptic flow and a structure suggestive of fragmentation of high pT partons. The monotonic rise of v2(pT) for pT<2 GeV/c is consistent with collective hydrodynamical flow calculations. At pT>3 GeV/c, a saturation of v2 is observed which persists up to pT=6 GeV/c.
Azimuthal anisotropy (v2) and two-particle angular correlations of high pT charged hadrons have been measured in Au+Au collisions at sqrt[sNN]=130 GeV for transverse momenta up to 6 GeV/c, where hard processes are expected to contribute significantly. The two-particle angular correlations exhibit elliptic flow and a structure suggestive of fragmentation of high pT partons. The monotonic rise of v2(pT) for pT<2 GeV/c is consistent with collective hydrodynamical flow calculations. At pT>3 GeV/c, a saturation of v2 is observed which persists up to pT=6 GeV/c.
Transverse mass and rapidity distributions for charged pions, charged kaons, protons, and antiprotons are reported for sqrt[sNN]=200 GeV pp and Au+Au collisions at Relativistic Heary Ion Collider (RHIC). Chemical and kinetic equilibrium model fits to our data reveal strong radial flow and long duration from chemical to kinetic freeze-out in central Au+Au collisions. The chemical freeze-out temperature appears to be independent of initial conditions at RHIC energies.
Measurements of the production of forward high-energy pi 0 mesons from transversely polarized proton collisions at sqrt[s]=200 GeV are reported. The cross section is generally consistent with next-to-leading order perturbative QCD calculations. The analyzing power is small at xF below about 0.3, and becomes positive and large at higher xF, similar to the trend in data at sqrt[s] <= 20 GeV. The analyzing power is in qualitative agreement with perturbative QCD model expectations. This is the first significant spin result seen for particles produced with pT>1 GeV/c at a polarized proton collider.
We report the first observations of the first harmonic (directed flow, v1) and the fourth harmonic (v4), in the azimuthal distribution of particles with respect to the reaction plane in Au+Au collisions at the BNL Relativistic Heavy Ion Collider (RHIC). Both measurements were done taking advantage of the large elliptic flow (v2) generated at RHIC. From the correlation of v2 with v1 it is determined that v2 is positive, or in-plane. The integrated v4 is about a factor of 10 smaller than v2. For the sixth (v6) and eighth (v8) harmonics upper limits on the magnitudes are reported.
Elliptic flow holds much promise for studying the early-time thermalization attained in ultrarelativistic nuclear collisions. Flow measurements also provide a means of distinguishing between hydrodynamic models and calculations which approach the low density (dilute gas) limit. Among the effects that can complicate the interpretation of elliptic flow measurements are azimuthal correlations that are unrelated to the reaction plane (nonflow correlations). Using data for Au + Au collisions at sqrt[sNN]=130 GeV from the STAR time projection chamber, it is found that four-particle correlation analyses can reliably separate flow and nonflow correlation signals. The latter account for on average about 15% of the observed second-harmonic azimuthal correlation, with the largest relative contribution for the most peripheral and the most central collisions. The results are also corrected for the effect of flow variations within centrality bins. This effect is negligible for all but the most central bin, where the correction to the elliptic flow is about a factor of 2. A simple new method for two-particle flow analysis based on scalar products is described. An analysis based on the distribution of the magnitude of the flow vector is also described.
We report the first observation of K*(892)0--> pi K in relativistic heavy ion collisions. The transverse momentum spectrum of (K*0+K*0)/2 from central Au+Au collisions at sqrt[sNN]=130 GeV is presented. The ratios of the K*0 yield derived from these data to the yields of negative hadrons, charged kaons, and phi mesons have been measured in central and minimum bias collisions and compared with model predictions and comparable e+e-, pp, and p-barp results. The data indicate no dramatic reduction of K*0 production in relativistic heavy ion collisions despite expected losses due to rescattering effects.
The STAR Collaboration reports the first observation of exclusive rho 0 photoproduction, AuAu-->AuAu rho 0, and rho 0 production accompanied by mutual nuclear Coulomb excitation, AuAu-->Au [star] Au [star] rho 0, in ultraperipheral heavy-ion collisions. The rho 0 have low transverse momenta, consistent with coherent coupling to both nuclei. The cross sections at sqrt[sNN]=130 GeV agree with theoretical predictions treating rho 0 production and Coulomb excitation as independent processes.
We report STAR results on the azimuthal anisotropy parameter v2 for strange particles K0S, Lambda , and Lambda -bar at midrapidity in Au+Au collisions at sqrt[sNN]=130 GeV at the Relativistic Heavy Ion Collider. The value of v2 as a function of transverse momentum, pt, of the produced particle and collision centrality is presented for both particles up to pt~3.0 GeV/c. A strong pt dependence in v2 is observed up to 2.0 GeV/c. The v2 measurement is compared with hydrodynamic model calculations. The physics implications of the pt integrated v2 magnitude as a function of particle mass are also discussed.
Inclusive transverse momentum distributions of charged hadrons within 0.2<pT<6.0 GeV/c have been measured over a broad range of centrality for Au+Au collisions at sqrt[sNN]=130 GeV. Hadron yields are suppressed at high pT in central collisions relative to peripheral collisions and to a nucleon-nucleon reference scaled for collision geometry. Peripheral collisions are not suppressed relative to the nucleon-nucleon reference. The suppression varies continuously at intermediate centralities. The results indicate significant nuclear medium effects on high-pT hadron production in heavy-ion collisions at high energy.
We report the first measurement of strange ( Lambda ) and antistrange ( Lambda -bar) baryon production from sqrt[sNN]=130 GeV Au+Au collisions at the Relativistic Heavy Ion Collider (RHIC). Rapidity density and transverse mass distributions at midrapidity are presented as a function of centrality. The yield of Lambda and Lambda -bar hyperons is found to be approximately proportional to the number of negative hadrons. The production of Lambda -bar hyperons relative to negative hadrons increases very rapidly with transverse momentum. The magnitude of the increase cannot be described by existing hadronic string fragmentation models alone.
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.
Two-pion correlation functions in Au+Au collisions at sqrt[sNN] = 130 GeV have been measured by the STAR (solenoidal tracker at RHIC) detector. The source size extracted by fitting the correlations grows with event multiplicity and decreases with transverse momentum. Anomalously large sizes or emission durations, which have been suggested as signals of quark-gluon plasma formation and rehadronization, are not observed. The Hanbury Brown-Twiss parameters display a weak energy dependence over a broad range in sqrt[sNN].
The first measurements of light antinucleus production in Au+Au collisions at the Relativistic Heavy-Ion Collider are reported. The observed production rates for d-bar and 3He-bar are much larger than in lower energy nucleus-nucleus collisions. A coalescence model analysis of the yields indicates that there is little or no increase in the antinucleon freeze-out volume compared to collisions at CERN SPS energy. These analyses also indicate that the 3He-bar freeze-out volume is smaller than the d-bar freeze-out volume.
We present the first measurement of midrapidity vector meson phi production in Au+Au collisions at RHIC (sqrt[sNN]=130 GeV) from the STAR detector. For the 11% highest multiplicity collisions, the slope parameter from an exponential fit to the transverse mass distribution is T=379±50(stat)±45(syst) MeV, the yield dN/dy=5.73±0.37(stat)±0.69(syst) per event, and the ratio N phi /Nh- is found to be 0.021±0.001(stat)±0.004(syst). The measured ratio N phi /Nh- and T for the phi meson at midrapidity do not change for the selected multiplicity bins.
Aim: Predicting future changes in species richness in response to climate change is one of the key challenges in biogeography and conservation ecology. Stacked species distribution models (S‐SDMs) are a commonly used tool to predict current and future species richness. Macroecological models (MEMs), regression models with species richness as response variable, are a less computationally intensive alternative to S‐SDMs. Here, we aim to compare the results of two model types (S‐SDMS and MEMs), for the first time for more than 14,000 species across multiple taxa globally, and to trace the uncertainty in future predictions back to the input data and modelling approach used.
Location: Global land, excluding Antarctica.
Taxon: Amphibians, birds and mammals.
Methods: We fitted S‐SDMs and MEMs using a consistent set of bioclimatic variables and model algorithms and conducted species richness predictions under current and future conditions. For the latter, we used four general circulation models (GCMs) under two representative concentration pathways (RCP2.6 and RCP6.0). Predicted species richness was compared between S‐SDMs and MEMs and for current conditions also to extent‐of‐occurrence (EOO) species richness patterns. For future predictions, we quantified the variance in predicted species richness patterns explained by the choice of model type, model algorithm and GCM using hierarchical cluster analysis and variance partitioning.
Results: Under current conditions, species richness predictions from MEMs and S‐SDMs were strongly correlated with EOO‐based species richness. However, both model types over‐predicted areas with low and under‐predicted areas with high species richness. Outputs from MEMs and S‐SDMs were also highly correlated among each other under current and future conditions. The variance between future predictions was mostly explained by model type.
Main conclusions: Both model types were able to reproduce EOO‐based patterns in global terrestrial vertebrate richness, but produce less collinear predictions of future species richness. Model type by far contributes to most of the variation in the different future species richness predictions, indicating that the two model types should not be used interchangeably. Nevertheless, both model types have their justification, as MEMs can also include species with a restricted range, whereas S‐SDMs are useful for looking at potential species‐specific responses.
Background: Isolated transient vertigo can be the only symptom of posterior circulation ischemia. Thus, it is important to differentiate isolated vertigo of a cerebrovascular origin from that of more benign origins, as patients with cerebral ischemia have a much higher risk for future stroke than do those with "peripheral" vertigo. The current study aims to identify risk factors for cerebrovascular origin of isolated transient vertigo, and for future cerebrovascular events.
Methods: From the files of 339 outpatients with isolated transient vertigo we extracted history, clinical and technical findings, diagnosis, and follow-up information on subsequent stroke or transient ischemic attack (TIA). Risk factors were analyzed using multivariate regression models (logistic or Cox) and reconfirmed in univariate analyses.
Results: On first presentation, 48 (14.2%) patients received the diagnosis "probable or definite cerebrovascular vertigo". During follow-up, 41 patients suffered stroke or TIA (event rate 7.9 per 100 person years, 95% confidence interval (CI) 5.5–10.4), 26 in the posterior circulation (event rate 4.8 per 100 person years, 95% CI 3.0–6.7). The diagnosis was not associated with follow-up cerebrovascular events. In multivariate models testing multiple potential determinants, only the presentation mode was consistently associated with the diagnosis and stroke risk: patients who presented because of vertigo (rather than reporting vertigo when they presented for other reasons) had a significantly higher risk for future stroke or TIA (p = 0.028, event rate 13.4 vs. 5.4 per 100 person years) and for future posterior circulation stroke or TIA (p = 0.044, event rate 7.8 vs. 3.5 per 100 person years).
Conclusions: We here report for the first time follow-up stroke rates in patients with transient isolated vertigo. In such patients, the identification of those with cerebrovascular origin remains difficult, and presentation mode was found to be the only consistent risk factor. Confirmation in an independent prospective sample is needed.
Background: In German breast cancer care, the S1-guidelines of the 1990s were substituted by national S3-guidelines in 2003. The application of guidelines became mandatory for certified breast cancer centers. The aim of the study was to assess guideline adherence according to time intervals and its impact on survival.
Methods: Women with primary breast cancer treated in three rural hospitals of one German geographical district were included. A cohort study design encompassed women from 1996–97 (N = 389) and from 2003–04 (N = 488). Quality indicators were defined along inpatient therapy sequences for each time interval and distinguished as guideline-adherent and guideline-divergent medical decisions. Based on all of the quality indicators, a binary overall adherence index was defined and served as a group indicator in multivariate Cox-regression models. A corrected group analysis estimated adjusted 5-year survival curves.
Results: From a total of 877 patients, 743 (85 %) and 504 (58 %) were included to assess 104 developed quality indicators and the resuming binary overall adherence index. The latter significantly increased from 13–15 % (1996–97) up to 33–35 % (2003–04). Within each time interval, no significant survival differences of guideline-adherent and -divergent treated patients were detected. Across time intervals and within the group of guideline-adherent treated patients only, survival increased but did not significantly differ between time intervals. Across time intervals and within the group of guideline-divergent treated patients only, survival increased and significantly differed between time intervals.
Conclusions: Infrastructural efforts contributed to the increase of process quality of the examined certified breast cancer center. Paradoxically, a systematic impact on 5-year survival has been observed for patients treated divergently from the guideline recommendations. This is an indicator for the appropriate application of guidelines. A maximization of guideline-based decisions instead of the ubiquitous demand of guideline adherence maximization is advocated.
Der nachfolgende Artikel stellt Regelungen zur Waldbehandlung dar, die nach den möglichen Auswirkungen bzw. Beeinträchtigungen des Lebensraumtypes durch forstliche Maßnahmen gegliedert sind. Die Auflistung für die einzelnen Lebenraumtypen ist jedoch nicht abschließend, sondern stellt nur eine Übersicht über die wesentlichen Maßnahmen einer Waldbehandlung dar.
LatticeQCD using OpenCL
(2011)
The Tarim River basin, located in Xinjiang, NW China, is the largest endorheic river basin in China and one of the largest in all of Central Asia. Due to the extremely arid climate, with an annual precipitation of less than 100 mm, the water supply along the Aksu and Tarim rivers solely depends on river water. This is linked to anthropogenic activities (e.g., agriculture) and natural and semi-natural ecosystems as both compete for water. The ongoing increase in water consumption by agriculture and other human activities in this region has been enhancing the competition for water between human needs and nature. Against this background, 11 German and 6 Chinese universities and research institutes have formed the consortium SuMaRiO (Sustainable Management of River Oases along the Tarim River; http://www.sumario.de), which aims to create a holistic picture of the availability of water resources in the Tarim River basin and the impacts on anthropogenic activities and natural ecosystems caused by the water distribution within the Tarim River basin. On the basis of the results from field studies and modeling approaches as well as from suggestions by the relevant regional stakeholders, a decision support tool (DST) will be implemented that will then assist stakeholders in balancing the competition for water, acknowledging the major external effects of water allocation to agriculture and to natural ecosystems. This consortium was formed in 2011 and is funded by the German Federal Ministry of Education and Research. As the data collection phase was finished this year, the paper presented here brings together the results from the fields from the disciplines of climate modeling, cryology, hydrology, agricultural sciences, ecology, geoinformatics, and social sciences in order to present a comprehensive picture of the effects of different water availability schemes on anthropogenic activities and natural ecosystems along the Tarim River. The second objective is to present the project structure of the whole consortium, the current status of work (i.e., major new results and findings), explain the foundation of the decision support tool as a key product of this project, and conclude with application recommendations for the region. The discharge of the Aksu River, which is the major tributary of the Tarim, has been increasing over the past 6 decades. From 1989 to 2011, agricultural area more than doubled: cotton became the major crop and there was a shift from small-scale to large-scale intensive farming. The ongoing increase in irrigated agricultural land leads to the increased threat of salinization and soil degradation caused by increased evapotranspiration. Aside from agricultural land, the major natural and semi-natural ecosystems are riparian (Tugai) forests, shrub vegetation, reed beds, and other grassland, as well as urban and peri-urban vegetation. Within the SuMaRiO cluster, focus has been set on the Tugai forests, with Populus euphratica as the dominant tree species, because these forests belong to the most productive and species-rich natural ecosystems of the Tarim River basin. At sites close to the groundwater, the annual stem diameter increments of Populus euphratica correlated with the river runoffs of the previous year. However, the natural river dynamics cease along the downstream course and thus hamper the recruitment of Populus euphratica. A study on the willingness to pay for the conservation of the natural ecosystems was conducted to estimate the concern of the people in the region and in China's capital. These household surveys revealed that there is a considerable willingness to pay for conservation of the natural ecosystems, with mitigation of dust and sandstorms considered the most important ecosystem service. Stakeholder dialogues contributed to creating a scientific basis for a sustainable management in the future.
It is long known that Kasugamycin inhibits translation of canonical transcripts containing a 5’-UTR with a Shine Dalgarno (SD) motif, but not that of leaderless transcripts. To gain a global overview of the influence of Kasugamycin on translation efficiencies, the changes of the translatome of Escherichia coli induced by a 10 minutes Kasugamycin treatment were quantified. The effect of Kasugamycin differed widely, 102 transcripts were at least twofold more sensitive to Kasugamycin than average, and 137 transcripts were at least twofold more resistant, and there was a more than 100-fold difference between the most resistant and the most sensitive transcript. The 5’-ends of 19 transcripts were determined from treated and untreated cultures, but Kasugamycin resistance did neither correlate with the presence or absence of a SD motif, nor with differences in 5’-UTR lengths or GC content. RNA Structure Logos were generated for the 102 Kasugamycin-sensitive and for the 137 resistant transcripts. For both groups a short Shine Dalgarno (SD) motif was retrieved, but no specific motifs associated with resistance or sensitivity could be found. Notably, this was also true for the region -3 to -1 upstream of the start codon and the presence of an extended SD motif, which had been proposed to result in Kasugamycin resistance. Comparison of the translatome results with the database RegulonDB showed that the transcript with the highest resistance was leaderless, but no further leaderless transcripts were among the resistant transcripts. Unexpectedly, it was found that translational coupling might be a novel feature that is associated with Kasugamycin resistance. Taken together, Kasugamycin has a profound effect on translational efficiencies of E. coli transcripts, but the mechanism of action is different than previously described.
In the context of Brexit, changes to the regulatory architecture of CCPs that empower the European securities markets regulator are under way to prevent the threat of a regulatory race to the bottom. However, this empowerment currently leaves the national supervision of common European rules within the EU intact. This policy letter argues that supervisory arbitrage is as much a threat within the EU as outside of it, wherefore a common supervision of CCP rules in the EU is called for. The paper traces the origins of the current set-up and criticizes the current regulatory proposal by the EU Commission as too cumbersome while discussing possible ways forward to achieve European supervision. In contrast to the current proposal of the Commission, we call for a unified supervision within ESMA, combined with a European fiscal backstop.
We report first results on elliptic flow of identified particles at midrapidity in Au+Au collisions at sqrt[sNN] = 130 GeV using the STAR TPC at RHIC. The elliptic flow as a function of transverse momentum and centrality differs significantly for particles of different masses. This dependence can be accounted for in hydrodynamic models, indicating that the system created shows a behavior consistent with collective hydrodynamical flow. The fit to the data with a simple model gives information on the temperature and flow velocities at freeze-out.
The minimum-bias multiplicity distribution and the transverse momentum and pseudorapidity distributions for central collisions have been measured for negative hadrons ( h-) in Au+Au interactions at sqrt[sNN] = 130 GeV. The multiplicity density at midrapidity for the 5% most central interactions is dNh-/d eta | eta = 0 = 280±1(stat)±20(syst), an increase per participant of 38% relative to pp-bar collisions at the same energy. The mean transverse momentum is 0.508±0.012 GeV/c and is larger than in central Pb+Pb collisions at lower energies. The scaling of the h- yield per participant is a strong function of pperp. The pseudorapidity distribution is almost constant within | eta |<1.
We report the first measurement of inclusive antiproton production at midrapidity in Au+Au collisions at sqrt[sNN] = 130 GeV by the STAR experiment at RHIC. The antiproton transverse mass distributions in the measured transverse momentum range of 0.25<pperp<0.95 GeV/c are found to fall less steeply for more central collisions. The extrapolated antiproton rapidity density is found to scale approximately with the negative hadron multiplicity density.
Microwave sensors in medical environments play a significant role due to the contact-less and non-invasive sensing mechanism to determine dielectric properties of tissue. In this work, a theranostic sensor based on Split Ring Resonators (SRRs) is presented that provides two operation modes to detect and treat tumor cells, exemplary in the liver. For the detection mode, resonance frequency changes due to abnormalities are evaluated, and in the treatment mode, microwave ablation is performed. The planar sensor structure can be integrated into a needle like a surgery tool that evokes challenges concerning size limitations and biocompatibility. To meet the size requirements and provide a reasonable operating frequency, properties of oval shaped SRRs are investigated. By elongating the radius of the SRR in one direction, the resonance frequency can be decreased significantly compared to circular SRR by a factor of two below 12 GHz. In order to validate the detection and treatment characteristics of the sensor, full wave simulations and measurements are examined. Clear resonance shifts are detected for loading the sensor structures with phantoms mimicking healthy and malignant tissue. For treatment mode evaluation, ex vivo beef liver tissue was ablated leading to a lesion zone 1.2 cm × 1 cm × 0.3 cm with a three minute exposure of maximum 2.1 W
An integrative correlation of myopathology, phenotype and genotype in late onset Pompe disease
(2019)
Aims: Pompe disease is caused by pathogenic mutations in the alpha 1,4‐glucosidase (GAA) gene and in patients with late onset Pome disease (LOPD), genotype–phenotype correlations are unpredictable. Skeletal muscle pathology includes glycogen accumulation and altered autophagy of various degrees. A correlation of the muscle morphology with clinical features and the genetic background in GAA may contribute to the understanding of the phenotypic variability.
Methods: Muscle biopsies taken before enzyme replacement therapy were analysed from 53 patients with LOPD. On resin sections, glycogen accumulation, fibrosis, autophagic vacuoles and the degree of muscle damage (morphology‐score) were analysed and the results were compared with clinical findings. Additional autophagy markers microtubule‐associated protein 1A/1B‐light chain 3, p62 and Bcl2‐associated athanogene 3 were analysed on cryosections from 22 LOPD biopsies.
Results: The myopathology showed a high variability with, in most patients, a moderate glycogen accumulation and a low morphology‐score. High morphology‐scores were associated with increased fibrosis and autophagy highlighting the role of autophagy in severe stages of skeletal muscle damage. The morphology‐score did not correlate with the patient's age at biopsy, disease duration, nor with the residual GAA enzyme activity or creatine‐kinase levels. In 37 patients with LOPD, genetic analysis identified the most frequent mutation, c.‐32‐13T>G, in 95%, most commonly in combination with c.525delT (19%). No significant correlation was found between the different GAA genotypes and muscle morphology type.
Conclusions: Muscle morphology in LOPD patients shows a high variability with, in most cases, moderate pathology. Increased pathology is associated with more fibrosis and autophagy.
Einleitung: Die konventionelle Galaktografie stellte jahrzehntelang das einzige bildgebende Verfahren zur Darstellung von Milchgängen in der Brust dar. Heute verfügen wir in der Diagnostik über ein multimodales Konzept aus hochauflösendem Ultraschall, der Magnetresonanz-(MR-)Mammografie und der Duktoskopie/Galaktoskopie mit Sensitivitäten und Spezifitäten bis zu 95%. Ziel unserer Untersuchung war es, erstmalig die Tomosynthesetechnik in der Galaktografie einzusetzen und die daraus generierten synthetischen digitalen 2-D-Vollfeld-Mammografien mit der etablierten Methode der duktusorientierten Sonografie zu vergleichen. Es sollen mit beiden Methoden invasive Mammakarzinome und deren Vorstufen wie duktale Carcinoma in situ (DCIS) sowie benigne Befunde erkannt werden. Material und Methoden: Wir führten bei 5 Patientinnen mit pathologischer Mamillensekretion sowohl eine duktusorientierte Sonografie, eine kontrastmittelunterstützte Galaktografie mithilfe der Tomosynthese in 3-D sowie auch den daraus generierten synthetischen digitalen 2-D-Vollfeld-Mammografien durch. Die Auswertung der unterschiedlichen Untersuchungsmodalitäten erfolgte durch 3 in der komplementären Mammadiagnostik erfahrene Untersucher (1, 5 und 15 Jahre) und wurde mit der endgültigen Histologie korreliert. Ergebnisse: Alle 3 Untersucher beurteilten unabhängig voneinander die Bilder des duktusorientierten Ultraschalls und der kontrastmittelunterstützten Galaktografie in Tomosynthesetechnik in 3-D und den daraus generierten, synthetischen digitalen 2-D-Vollfeld-Mammografien. Die Ergebnisse wurden mit den histopathologischen Befunden der Operationspräparate korreliert, wobei sich bei den 5 Patientinnen 1 invasives Mammakarzinom, 2-mal ein duktales Carcinoma in situ (DCIS) und 2 benigne Befunde ergaben. Alle drei Untersucher lagen bei der Verdachtsdiagnose in der Standardbildgebung der duktusorientierten Sonografie seltener richtig als bei der erstmalig durchgeführten, kontrastmittelunterstützten Galaktografie in Tomosynthesetechnik und den daraus generierten, synthetischen digitalen 2-D-Vollfeld-Mammografien. Schlussfolgerung: Erstmalig wurde die Brusttomosynthese in der Galaktografie (Galaktomosynthese) eingesetzt und ermöglichte eine digitale, 3-dimensionale Darstellung von suspekten Befunden. Zusammen mit den daraus synthetisierten, digitalen 2-D-Vollfeld-Mammografien könnte dies in Zukunft eine sinnvolle Ergänzung der komplementären Mammadiagnostik sein – und eine Renaissance dieser Methode. Im Vergleich mit dem duktusorientierten Ultraschall in Hochauflösung erzielten die Untersucher mit der kontrastmittelunterstützten Galaktografie in Tomosynthesetechnik und den daraus generierten, synthetischen digitalen 2-D-Vollfeld-Mammografien bessere Ergebnisse in Korrelation mit den histopathologischen Befunden.
Introduction: For decades, conventional galactography was the only imaging technique capable of showing the mammary ducts. Today, diagnosis is based on a multimodal concept which combines high-resolution ultrasound with magnetic resonance (MR) mammography and ductoscopy/galactoscopy and has a sensitivity and specificity of up to 95%. This study used tomosynthesis in galactography for the first time and compared the synthetic digital 2D full-field mammograms generated with this technique with the images created using the established method of ductal sonography. Both methods should be able to detect invasive breast cancers and their precursors such as ductal carcinoma in situ (DCIS) as well as being able to identify benign findings.
Material and Methods: Five patients with pathological nipple discharge were examined using ductal sonography, contrast-enhanced 3D galactography with tomosynthesis and the synthetic digital 2D full-field mammograms generated with the latter method. Evaluation of the images created with the different imaging modalities was done by three investigators with varying levels of experience with complementary breast diagnostics (1, 5 and 15 years), and their evaluations were compared with the histological findings.
Results: All 3 investigators independently evaluated the images created with ductal sonography, contrast-enhanced 3D galactography with tomosynthesis, and generated synthetic digital 2D full-field mammograms. Their evaluations were compared with the histopathological assessment of the surgical specimens resected from the 5 patients. There was 1 case of invasive breast cancer, 2 cases with ductal carcinoma in situ and 2 cases with benign findings. All 3 investigators made more mistakes when they used the standard imaging technique of ductal sonography to diagnose suspicious lesions than when they used contrast-enhanced galactography with tomosynthesis and the generated synthetic digital 2D full-field mammograms.
Conclusion: This is the first time breast tomosynthesis was used in galactography (galactomosynthesis) to create digital 3-dimensional images of suspicious findings. When used together with the generated synthetic digital 2D full-field mammograms, it could be a useful complementary procedure for the diagnosis of breast anomalies and could herald a renaissance of this method. Compared with high-resolution ductal ultrasound, the investigators achieved better results with contrast-enhanced galactography using tomosynthesis and the generated synthetic digital 2D full-field mammograms, as confirmed by histopathological findings.
We investigate the impact of reporting regulation on corporate innovation. Exploiting thresholds in Europe’s regulation and a major enforcement reform in Germany, we find that forcing firms to publicly disclose their financial statements discourages innovative activities. Our evidence suggests that reporting regulation has significant real effects by imposing proprietary costs on innovative firms, which in turn diminish their incentives to innovate. At the industry level, positive information spillovers (e.g., to competitors, suppliers, and customers) appear insufficient to compensate the negative direct effect on the prevalence of innovative activity. The spillovers instead appear to concentrate innovation among a few large firms in a given industry. Thus, financial reporting regulation has important aggregate and distributional effects on corporate innovation.
Although chest radiograph (CXR) is commonly used in diagnosing pediatric community acquired pneumonia (pCAP), limited data on interobserver agreement among radiologists exist. PedCAPNETZ is a prospective, observational, and multicenter study on pCAP. N = 233 CXR from patients with clinical diagnosis of pCAP were retrieved and n = 12 CXR without pathological findings were added. All CXR were interpreted by a radiologist at the site of recruitment and by two external, blinded pediatric radiologists. To evaluate interobserver agreement, the reporting of presence or absence of pCAP in CXR was analyzed, and prevalence and bias-adjusted kappa (PABAK) statistical testing was applied. Overall, n = 190 (82%) of CXR were confirmed as pCAP by two external pediatric radiologists. Compared with patients with pCAP negative CXR, patients with CXR-confirmed pCAP displayed higher C-reactive protein levels and a longer duration of symptoms before enrollment (p < .007). Further parameters, that is, age, respiratory rate, and oxygen saturation showed no significant difference. The interobserver agreement between the onsite radiologists and each of the two independent pediatric radiologists for the presence of pCAP was poor to fair (69%; PABAK = 0.39% and 76%; PABAK = 0.53, respectively). The concordance between the external radiologists was fair (81%; PABAK = 0.62). With regard to typical CXR findings for pCAP, chance corrected interrater agreement was highest for pleural effusions, infiltrates, and consolidations and lowest for interstitial patterns and peribronchial thickening. Our data show a poor interobserver agreement in the CXR-based diagnosis of pCAP and emphasized the need for harmonized interpretation standards.
Very-long-baseline interferometry (VLBI) observations of active galactic nuclei at millimetre wavelengths have the power to reveal the launching and initial collimation region of extragalactic radio jets, down to 10–100 gravitational radii (rg ≡ GM/c2) scales in nearby sources. Centaurus A is the closest radio-loud source to Earth. It bridges the gap in mass and accretion rate between the supermassive black holes (SMBHs) in Messier 87 and our Galactic Centre. A large southern declination of −43° has, however, prevented VLBI imaging of Centaurus A below a wavelength of 1 cm thus far. Here we show the millimetre VLBI image of the source, which we obtained with the Event Horizon Telescope at 228 GHz. Compared with previous observations, we image the jet of Centaurus A at a tenfold higher frequency and sixteen times sharper resolution and thereby probe sub-lightday structures. We reveal a highly collimated, asymmetrically edge-brightened jet as well as the fainter counterjet. We find that the source structure of Centaurus A resembles the jet in Messier 87 on ~500 rg scales remarkably well. Furthermore, we identify the location of Centaurus A’s SMBH with respect to its resolved jet core at a wavelength of 1.3 mm and conclude that the source’s event horizon shadow should be visible at terahertz frequencies. This location further supports the universal scale invariance of black holes over a wide range of masses.
Zoos attract millions of visitors every year, many of whom are schoolchildren. For this reason, zoos are important institutions for the environmental education of future generations. Empirical studies on the educational impact of environmental education programs in zoos are still rare. To address this issue, we conducted two studies: In study 1, we investigated students’ interests in different biological topics, including zoos (n = 1,587). Data analysis of individual topics revealed large differences of interest, with advanced students showing less interest in zoos. In study 2, we invited school classes of this age group to visit different guided tours at the zoo and tested connection to nature before and after each educational intervention (n = 608). The results showed that the guided tours are an effective tool to raise students’ connection to nature. Add-on components have the potential to further promote connection to nature. The education programs are most effective with students with a low initial nature connection.
Extensive black shale deposits formed in the Early Cretaceous South Atlantic, supporting the notion that this emerging ocean basin was a globally important site of organic carbon burial. The magnitude of organic carbon burial in marine basins is known to be controlled by various tectonic, oceanographic, hydrological, and climatic processes acting on different temporal and spatial scales, the nature and relative importance of which are poorly understood for the young South Atlantic. Here we present new bulk and molecular geochemical data from an Aptian–Albian sediment record recovered from the deep Cape Basin at Deep Sea Drilling Project (DSDP) Site 361, which we combine with general circulation model results to identify driving mechanisms of organic carbon burial. A multimillion-year decrease (i.e., Early Aptian–Albian) in organic carbon burial, reflected in a lithological succession of black shale, gray shale, and red beds, was caused by increasing bottom water oxygenation due to abating hydrographic restriction via South Atlantic–Southern Ocean gateways. These results emphasize basin evolution and ocean gateway development as a decisive primary control on enhanced organic carbon preservation in the Cape Basin at geological timescales (> 1 Myr). The Early Aptian black shale sequence comprises alternations of shales with high (> 6 %) and relatively low (∼ 3.5 %) organic carbon content of marine sources, the former being deposited during the global Oceanic Anoxic Event (OAE) 1a, as well as during repetitive intervals before and after OAE 1a. In all cases, these short-term intervals of enhanced organic carbon burial coincided with strong influxes of sediments derived from the proximal African continent, indicating closely coupled climate–land–ocean interactions. Supported by our model results, we show that fluctuations in weathering-derived nutrient input from the southern African continent, linked to changes in orbitally driven humidity and aridity, were the underlying drivers of repetitive episodes of enhanced organic carbon burial in the deep Cape Basin. These results suggest that deep marine environments of emerging ocean basins responded sensitively and directly to short-term fluctuations in riverine nutrient fluxes. We explain this relationship using the lack of wide and mature continental shelf seas that could have acted as a barrier or filter for nutrient transfer from the continent into the deep ocean.
Extensive black shale deposits formed in the Early Cretaceous South Atlantic, supporting the notion that this emerging ocean basin was a globally important site of organic carbon burial. The magnitude of organic carbon burial in marine basins is known to be controlled by various tectonic, oceanographic, hydrological, and climatic processes acting on different temporal and spatial scales, the nature and relative importance of which are poorly understood for the young South Atlantic. Here we present new bulk and molecular geochemical data from an Aptian–Albian sediment record recovered from the deep Cape Basin at Deep Sea Drilling Project (DSDP) Site 361, which we combine with general circulation model results to identify driving mechanisms of organic carbon burial. A multi-million year decrease (i.e. Early Aptian–Albian) in organic carbon burial, reflected in a lithological succession of black shale, gray shale, and red beds, was caused by increasing bottom water oxygenation due to abating tectonic restriction via South Atlantic-Southern Ocean gateways. These results emphasize basin evolution and ocean gateway development as a decisive primary control on enhanced organic carbon preservation in the Cape Basin at geological time scales (>1 Myr). The Early Aptian black shale sequence comprises alternations of shales with high (>5%) and relatively low (~3%) organic carbon content of marine sources, the former being deposited during the global Oceanic Anoxic Event (OAE) 1a, as well as during repetitive events before and after OAE 1a. In all cases, these short-term events of enhanced organic carbon burial coincided with strong influxes of sediments derived from the proximal African continent, indicating closely coupled climate–land–ocean interactions. Supported by our model results, we propose that fluctuations in weathering-derived nutrient input from the southern African continent, linked to fluctuations in pCO2 and/or orbitally driven humidity/aridity, were the underlying drivers of short-term organic carbon burial in the deep Cape Basin. These results suggest that deep marine environments of emerging ocean basins responded sensitively and directly to short term fluctuations in riverine nutrient fluxes. We explain this relationship by the lack of wide and mature continental shelf seas that could have acted as a barrier or filter for nutrient transfer from the continent into the deep ocean.
Two-particle correlation functions of negative hadrons over wide phase space, and transverse mass spectra of negative hadrons and deuterons near mid-rapidity have been measured in central Pb+Pb collisions at 158 GeV per nucleon by the NA49 experiment at the CERN SPS. A novel Coulomb correction procedure for the negative two-particle correlations is employed making use of the measured oppositely charged particle correlation. Within an expanding source scenario these results are used to extract the dynamic characteristics of the hadronic source, resolving the ambiguities between the temperature and transverse expansion velocity of the source, that are unavoidable when single and two particle spectra are analysed separately. The source shape, the total duration of the source expansion, the duration of particle emission, the freeze-out temperature and the longitudinal and transverse expansion velocities are deduced.
We report measurements of Xi and Xi-bar hyperon absolute yields as a function of rapidity in 158 GeV/c Pb+Pb collisions. At midrapidity, dN/dy = 2.29 +/- 0.12 for Xi, and 0.52 +/- 0.05 for Xi-bar, leading to the ratio of Xi-bar/Xi = 0.23 +/- 0.03. Inverse slope parameters fitted to the measured transverse mass spectra are of the order of 300 MeV near mid-rapidity. The estimated total yield of Xi particles in Pb+Pb central interactions amounts to 7.4 +/- 1.0 per collision. Comparison to Xi production in properly scaled p+p reactions at the same energy reveals a dramatic enhancement (about one order of magnitude) of Xi production in Pb+Pb central collisions over elementary hadron interactions.
The directed and elliptic flow of protons and charged pions has been observed from the semi-central collisions of a 158 GeV/nucleon Pb beam with a Pb target. The rapidity and transverse momentum dependence of the flow has been measured. The directed flow of the pions is opposite to that of the protons but both exhibit negative flow at low pt. The elliptic flow of both is fairly independent of rapidity but rises with pt. PACS numbers: 25.75.-q, 25.75.Ld
Objective: Pancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC; however, subtypes of the disease exist, which exhibit extensive resistance to such therapies. Genomic MYC amplifications represent a distinct subset of PDAC with an aggressive tumour biology. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. The aim of the study was to find and to target MYC-associated dependencies.
Design: We analysed human PDAC gene expression datasets. Results were corroborated by the analysis of the small ubiquitin-like modifier (SUMO) pathway in a large PDAC cohort using immunohistochemistry. A SUMO inhibitor was used and characterised using human and murine two-dimensional, organoid and in vivo models of PDAC.
Results: We observed that MYC is connected to the SUMOylation machinery in PDAC. Components of the SUMO pathway characterise a PDAC subtype with a dismal prognosis and we provide evidence that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition.
Conclusion: SUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype.
Background: During the COVID-19 pandemic, decreased volumes of acute stroke admissions were reported. We aimed to examine whether subarachnoid hemorrhage (SAH) volumes demonstrated similar declines in our department. Furthermore, the impact of pandemic on disease progression should be analyzed.
Methods: We conducted a retrospective study in neurosurgical department of university hospital Frankfurt including patients with the diagnosis of aneurysmal SAH during the first year of COVID-pandemic. One year cumulative volume for SAH hospitalization procedures were compared to the one-year period before (03/2020–02/2021 versus 03/2019–02/2020) and the last 5 pre-COVID-pandemic years (2015-2020). All relevant patient characteristics concerning family history, disease history, clinical condition at admission, active/past COVID-infection, treatment management, complications and outcome were analyzed.
Results: There was a decline in SAH hospitalizations, with 84 admissions in the year immediately before and 56 admissions during the pandemic, without reaching a significance. No significant difference in analyzed patient characteristics including clinical condition at onset, treatment, complications and outcome, between 56 SAH patients admitted during COVID pandemic and treated patients in the last 5 years in pre-COVID period were found. Using a multivariable analysis, we detected young age (p<0.05;OR4,2) and no existence of early hydrocephalus (p<0.05;OR0,13) as important factors for a favorable outcome (mRS≤0-2) after aSAH during the COVID-pandemic. A past COVID-infection was detected in young patients suffering from aSAH (Age< 50years, p<0.05;OR10,5) with increased rate of cerebral vasospasm after SAH onset (p<0.05;OR26). Nevertheless, past COVID-infection did not reach a significance as a high risk factor for unfavorable outcome.
Conclusion: There was a relative decrease in the volume of SAH during the COVID-19 pandemic. Despite of extremely different conditions of hospitalization, there was no impairing significant effect on treatment and outcome of admitted SAH patients. A past COVID-infection seemed not to be a relevant limiting factor concerning favorable outcome.
Background: Perioperative anaemia leads to impaired oxygen supply with a risk of vital organ ischaemia. In healthy and fit individuals, anaemia can be compensated by several mechanisms. Elderly patients, however, have less compensatory mechanisms because of multiple co-morbidities and age-related decline of functional reserves. The purpose of the study is to evaluate whether elderly surgical patients may benefit from a liberal red blood cell (RBC) transfusion strategy compared to a restrictive transfusion strategy.
Methods: The LIBERAL Trial is a prospective, randomized, multicentre, controlled clinical phase IV trial randomising 2470 elderly (≥ 70 years) patients undergoing intermediate- or high-risk non-cardiac surgery. Registered patients will be randomised only if Haemoglobin (Hb) reaches ≤9 g/dl during surgery or within 3 days after surgery either to the LIBERAL group (transfusion of a single RBC unit when Hb ≤ 9 g/dl with a target range for the post-transfusion Hb level of 9–10.5 g/dl) or the RESTRICTIVE group (transfusion of a single RBC unit when Hb ≤ 7.5 g/dl with a target range for the post-transfusion Hb level of 7.5–9 g/dl). The intervention per patient will be followed until hospital discharge or up to 30 days after surgery, whichever occurs first. The primary efficacy outcome is defined as a composite of all-cause mortality, acute myocardial infarction, acute ischaemic stroke, acute kidney injury (stage III), acute mesenteric ischaemia and acute peripheral vascular ischaemia within 90 days after surgery. Infections requiring iv antibiotics with re-hospitalisation are assessed as important secondary endpoint. The primary endpoint will be analysed by logistic regression adjusting for age, cancer surgery (y/n), type of surgery (intermediate- or high-risk), and incorporating centres as random effect.
Discussion: The LIBERAL-Trial will evaluate whether a liberal transfusion strategy reduces the occurrence of major adverse events after non-cardiac surgery in the geriatric population compared to a restrictive strategy within 90 days after surgery.
Trial registration: ClinicalTrials.gov (identifier: NCT03369210).
Rho-family GTPases like RhoA and Rac-1 are potent regulators of cellular signaling that control gene expression, migration and inflammation. Activation of Rho-GTPases has been linked to podocyte dysfunction, a feature of chronic kidney diseases (CKD). We investigated the effect of Rac-1 and Rho kinase (ROCK) inhibition on progressive renal failure in mice and studied the underlying mechanisms in podocytes. SV129 mice were subjected to 5/6-nephrectomy which resulted in arterial hypertension and albuminuria. Subgroups of animals were treated with the Rac-1 inhibitor EHT1846, the ROCK inhibitor SAR407899 and the ACE inhibitor Ramipril. Only Ramipril reduced hypertension. In contrast, all inhibitors markedly attenuated albumin excretion as well as glomerular and tubulo-interstitial damage. The combination of SAR407899 and Ramipril was more effective in preventing albuminuria than Ramipril alone. To study the involved mechanisms, podocytes were cultured from SV129 mice and exposed to static stretch in the Flexcell device. This activated RhoA and Rac-1 and led via TGFβ to apoptosis and a switch of the cells into a more mesenchymal phenotype, as evident from loss of WT-1 and nephrin and induction of α-SMA and fibronectin expression. Rac-1 and ROCK inhibition as well as blockade of TGFβ dramatically attenuated all these responses. This suggests that Rac-1 and RhoA are mediators of podocyte dysfunction in CKD. Inhibition of Rho-GTPases may be a novel approach for the treatment of CKD.
Endocannabinoids are important lipid-signaling mediators. Both protective and deleterious effects of endocannabinoids in the cardiovascular system have been reported but the mechanistic basis for these contradicting observations is unclear. We set out to identify anti-inflammatory mechanisms of endocannabinoids in the murine aorta and in human vascular smooth muscle cells (hVSMC). In response to combined stimulation with cytokines, IL-1β and TNFα, the murine aorta released several endocannabinoids, with anandamide (AEA) levels being the most significantly increased. AEA pretreatment had profound effects on cytokine-induced gene expression in hVSMC and murine aorta. As revealed by RNA-Seq analysis, the induction of a subset of 21 inflammatory target genes, including the important cytokine CCL2 was blocked by AEA. This effect was not mediated through AEA-dependent interference of the AP-1 or NF-κB pathways but rather through an epigenetic mechanism. In the presence of AEA, ATAC-Seq analysis and chromatin-immunoprecipitations revealed that CCL2 induction was blocked due to increased levels of H3K27me3 and a decrease of H3K27ac leading to compacted chromatin structure in the CCL2 promoter. These effects were mediated by recruitment of HDAC4 and the nuclear corepressor NCoR1 to the CCL2 promoter. This study therefore establishes a novel anti-inflammatory mechanism for the endogenous endocannabinoid AEA in vascular smooth muscle cells. Furthermore, this work provides a link between endogenous endocannabinoid signaling and epigenetic regulation.