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In this meeting report, particularly addressing the topic of protection of the cardiovascular system from ischemia/reperfusion injury, highlights are presented that relate to conditioning strategies of the heart with respect to molecular mechanisms and outcome in patients’ cohorts, the influence of co-morbidities and medications, as well as the contribution of innate immune reactions in cardioprotection. Moreover, developmental or systems biology approaches bear great potential in systematically uncovering unexpected components involved in ischemia–reperfusion injury or heart regeneration. Based on the characterization of particular platelet integrins, mitochondrial redox-linked proteins, or lipid-diol compounds in cardiovascular diseases, their targeting by newly developed theranostics and technologies opens new avenues for diagnosis and therapy of myocardial infarction to improve the patients’ outcome.
Background: Intracerebral haemorrhage growth is associated with poor clinical outcome and is a therapeutic target for improving outcome. We aimed to determine the absolute risk and predictors of intracerebral haemorrhage growth, develop and validate prediction models, and evaluate the added value of CT angiography.
Methods: In a systematic review of OVID MEDLINE—with additional hand-searching of relevant studies' bibliographies— from Jan 1, 1970, to Dec 31, 2015, we identified observational cohorts and randomised trials with repeat scanning protocols that included at least ten patients with acute intracerebral haemorrhage. We sought individual patient-level data from corresponding authors for patients aged 18 years or older with data available from brain imaging initially done 0·5–24 h and repeated fewer than 6 days after symptom onset, who had baseline intracerebral haemorrhage volume of less than 150 mL, and did not undergo acute treatment that might reduce intracerebral haemorrhage volume. We estimated the absolute risk and predictors of the primary outcome of intracerebral haemorrhage growth (defined as >6 mL increase in intracerebral haemorrhage volume on repeat imaging) using multivariable logistic regression models in development and validation cohorts in four subgroups of patients, using a hierarchical approach: patients not taking anticoagulant therapy at intracerebral haemorrhage onset (who constituted the largest subgroup), patients taking anticoagulant therapy at intracerebral haemorrhage onset, patients from cohorts that included at least some patients taking anticoagulant therapy at intracerebral haemorrhage onset, and patients for whom both information about anticoagulant therapy at intracerebral haemorrhage onset and spot sign on acute CT angiography were known.
Findings: Of 4191 studies identified, 77 were eligible for inclusion. Overall, 36 (47%) cohorts provided data on 5435 eligible patients. 5076 of these patients were not taking anticoagulant therapy at symptom onset (median age 67 years, IQR 56–76), of whom 1009 (20%) had intracerebral haemorrhage growth. Multivariable models of patients with data on antiplatelet therapy use, data on anticoagulant therapy use, and assessment of CT angiography spot sign at symptom onset showed that time from symptom onset to baseline imaging (odds ratio 0·50, 95% CI 0·36–0·70; p<0·0001), intracerebral haemorrhage volume on baseline imaging (7·18, 4·46–11·60; p<0·0001), antiplatelet use (1·68, 1·06–2·66; p=0·026), and anticoagulant use (3·48, 1·96–6·16; p<0·0001) were independent predictors of intracerebral haemorrhage growth (C-index 0·78, 95% CI 0·75–0·82). Addition of CT angiography spot sign (odds ratio 4·46, 95% CI 2·95–6·75; p<0·0001) to the model increased the C-index by 0·05 (95% CI 0·03–0·07).
Interpretation: In this large patient-level meta-analysis, models using four or five predictors had acceptable to good discrimination. These models could inform the location and frequency of observations on patients in clinical practice, explain treatment effects in prior randomised trials, and guide the design of future trials.
Funding: UK Medical Research Council and British Heart Foundation.
Immunotherapy with oncolytic herpes simplex virus-1 therapy offers an innovative, targeted, less-toxic approach for treating brain tumors. However, a major obstacle in maximizing oncolytic virotherapy is a lack of comprehensive understanding of the underlying mechanisms that unfold in CNS tumors/associated microenvironments after infusion of virus. We demonstrate that our multiplex biomarker screening platform comprehensively informs changes in both topographical location and functional states of resident/infiltrating immune cells that play a role in neuropathology after treatment with HSV G207 in a pediatric Phase 1 patient. Using this approach, we identified robust infiltration of CD8+ T cells suggesting activation of the immune response following virotherapy; however there was a corresponding upregulation of checkpoint proteins PD-1, PD-L1, CTLA-4, and IDO revealing a potential role for checkpoint inhibitors. Such work may ultimately lead to an understanding of the governing pathobiology of tumors, thereby fostering development of novel therapeutics tailored to produce optimal responses.
The elliptic-flow ratio of neutrons with respect to protons or light complex particles in reactions of heavy ions at pre-relativistic energies has been proposed as an observable sensitive to the strength of the symmetry term of the nuclear equation of state at supra-saturation densities. In the ASY-EOS experiment at the GSI laboratory, flows of neutrons and light charged particles were measured for 197Au+197Au collisions at 400 MeV/nucleon. Flow results obtained for the Au+Au system, in comparison with predictions of the UrQMD transport model, confirm the moderately soft to linear density dependence of the symmetry energy deduced from the earlier FOPI-LAND data.
An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.
A measurement of dijet correlations in p–Pb collisions at √sNN = 5.02 TeV with the ALICE detector is presented. Jets are reconstructed from charged particles measured in the central tracking detectors and neutral energy deposited in the electromagnetic calorimeter. The transverse momentum of the full jet (clustered from charged and neutral constituents) and charged jet (clustered from charged particles only) is corrected event-by-event for the contribution of the underlying event, while corrections for underlying event fluctuations and finite detector resolution are applied on an inclusive basis. A projection of the dijet transverse momentum, kTy = pch+ne T,jet sin(ϕdijet) with ϕdijet the azimuthal angle between a full and charged jet and pch+ne T,jet the transverse momentum of the full jet, is used to study nuclear matter effects in p–Pb collisions. This observable is sensitive to the acoplanarity of dijet production and its potential modification in p–Pb collisions with respect to pp collisions. Measurements of the dijet kTy as a function of the transverse momentum of the full and recoil charged jet, and the event multiplicity are presented. No significant modification of kTy due to nuclear matter effects in p–Pb collisions with respect to the event multiplicity or a PYTHIA8 reference is observed.
The transverse momentum (pT) spectrum and nuclear modification factor (RAA) of reconstructed jets in 0–10% and 10–30% central Pb–Pb collisions at √sNN = 2.76 TeV were measured. Jets were reconstructed using the anti-kT jet algorithm with a resolution parameter of R = 0.2 from charged and neutral particles, utilizing the ALICE tracking detectors and Electromagnetic Calorimeter (EMCal). The jet pT spectra are reported in the pseudorapidity interval of |ηjet| < 0.5 for 40 < pT, jet < 120 GeV/c in 0–10% and for 30 < pT, jet < 100 GeV/c in 10–30% collisions. Reconstructed jets were required to contain a leading charged particle with pT > 5 GeV/c to suppress jets constructed from the combinatorial background in Pb–Pb collisions. The leading charged particle requirement applied to jet spectra both in pp and Pb–Pb collisions had a negligible effect on the RAA. The nuclear modification factor RAA was found to be 0.28 ± 0.04 in 0–10% and 0.35 ± 0.04 in 10–30% collisions, independent of pT, jet within the uncertainties of the measurement. The observed suppression is in fair agreement with expectations from two model calculations with different approaches to jet quenching.
Angular correlations between charged trigger and associated particles are measured by the ALICE detector in p–Pb collisions at a nucleon–nucleon centre-of-mass energy of 5.02 TeV for transverse momentum ranges within 0.5<pT,assoc<pT,trig<4 GeV/c. The correlations are measured over two units of pseudorapidity and full azimuthal angle in different intervals of event multiplicity, and expressed as associated yield per trigger particle. Two long-range ridge-like structures, one on the near side and one on the away side, are observed when the per-trigger yield obtained in low-multiplicity events is subtracted from the one in high-multiplicity events. The excess on the near-side is qualitatively similar to that recently reported by the CMS Collaboration, while the excess on the away-side is reported for the first time. The two-ridge structure projected onto azimuthal angle is quantified with the second and third Fourier coefficients as well as by near-side and away-side yields and widths. The yields on the near side and on the away side are equal within the uncertainties for all studied event multiplicity and pT bins, and the widths show no significant evolution with event multiplicity or pT. These findings suggest that the near-side ridge is accompanied by an essentially identical away-side ridge.
The production of muons from heavy-flavour hadron decays in p–Pb collisions at t √sNN=5.02 TeV was studied for 2<pT<16 GeV/c with the ALICE detector at the CERN LHC. The measurement was performed at forward (p-going direction) and backward (Pb-going direction) rapidity, in the ranges of rapidity in the centre-of-mass system (cms) 2.03<ycms<3.53 and −4.46<ycms<−2.96, respectively. The production cross sections and nuclear modification factors are presented as a function of transverse momentum (pT). At forward rapidity, the nuclear modification factor is compatible with unity while at backward rapidity, in the interval 2.5<pT<3.5 GeV/c, it is above unity by more than 2σ. The ratio of the forward-to-backward production cross sections is also measured in the overlapping interval 2.96<|ycms|<3.53 and is smaller than unity by 3.7σ in 2.5<pT<3.5 GeV/c. The data are described by model calculations including cold nuclear matter effects.
Measurements of the production cross sections of prompt D0, D+, D∗+, D+s, Λ+c, and Ξ+c charm hadrons at midrapidity in proton−proton collisions at s√=13 TeV with the ALICE detector are presented. The D-meson cross sections as a function of transverse momentum (pT) are provided with improved precision and granularity. The ratios of pT-differential meson production cross sections based on this publication and on measurements at different rapidity and collision energy provide a constraint on gluon parton distribution functions at low values of Bjorken-x (10−5−10−4). The measurements of Λ+c (Ξ+c) baryon production extend the measured pT intervals down to pT=0(3)~GeV/c. These measurements are used to determine the charm-quark fragmentation fractions and the cc¯¯ production cross section at midrapidity (|y|<0.5) based on the sum of the cross sections of the weakly-decaying ground-state charm hadrons D0, D+, D+s, Λ+c, Ξ0c and, for the first time, Ξ+c, and of the strongly-decaying J/psi mesons. The first measurements of Ξ+c and Σ0,++c fragmentation fractions at midrapidity are also reported. A significantly larger fraction of charm quarks hadronising to baryons is found compared to e+e− and ep collisions. The cc¯¯ production cross section at midrapidity is found to be at the upper bound of state-of-the-art perturbative QCD calculations.
Measurements of the production cross sections of prompt D0, D+, D∗+, D+s, Λ+c, and Ξ+c charm hadrons at midrapidity in proton−proton collisions at s√=13 TeV with the ALICE detector are presented. The D-meson cross sections as a function of transverse momentum (pT) are provided with improved precision and granularity. The ratios of pT-differential meson production cross sections based on this publication and on measurements at different rapidity and collision energy provide a constraint on gluon parton distribution functions at low values of Bjorken-x (10−5−10−4). The measurements of Λ+c (Ξ+c) baryon production extend the measured pT intervals down to pT=0(3)~GeV/c. These measurements are used to determine the charm-quark fragmentation fractions and the cc¯¯ production cross section at midrapidity (|y|<0.5) based on the sum of the cross sections of the weakly-decaying ground-state charm hadrons D0, D+, D+s, Λ+c, Ξ0c and, for the first time, Ξ+c, and of the strongly-decaying J/psi mesons. The first measurements of Ξ+c and Σ0,++c fragmentation fractions at midrapidity are also reported. A significantly larger fraction of charm quarks hadronising to baryons is found compared to e+e− and ep collisions. The cc¯¯ production cross section at midrapidity is found to be at the upper bound of state-of-the-art perturbative QCD calculations.
The elliptic flow (v2) of D0 mesons from beauty-hadron decays (non-prompt D0) was measured in midcentral (30-50%) Pb-Pb collisions at a centre-of-mass energy per nucleon pair sNN−−−√ = 5.02 TeV with the ALICE detector at the LHC. The D0 mesons were reconstructed at midrapidity (|y|<0.8) from their hadronic decay D0→K−π+, in the transverse momentum interval 2<pT<12 GeV/c. The result indicates a positive v2 for non-prompt D0 mesons with a significance of 2.7σ. The non-prompt D0-meson v2 is lower than that of prompt non-strange D mesons with 3.2σ significance in 2<pT<8 GeV/c, and compatible with the v2 of beauty-decay electrons. Theoretical calculations of beauty-quark transport in a hydrodynamically expanding medium describe the measurement within uncertainties.
The elliptic flow (v2) of D0 mesons from beauty-hadron decays (non-prompt D0) was measured in midcentral (30-50%) Pb-Pb collisions at a centre-of-mass energy per nucleon pair sNN−−−√ = 5.02 TeV with the ALICE detector at the LHC. The D0 mesons were reconstructed at midrapidity (|y|<0.8) from their hadronic decay D0→K−π+, in the transverse momentum interval 2<pT<12 GeV/c. The result indicates a positive v2 for non-prompt D0 mesons with a significance of 2.7σ. The non-prompt D0-meson v2 is lower than that of prompt non-strange D mesons with 3.2σ significance in 2<pT<8 GeV/c, and compatible with the v2 of beauty-decay electrons. Theoretical calculations of beauty-quark transport in a hydrodynamically expanding medium describe the measurement within uncertainties.
Measurements of charged-particle production in pp, p−Pb, and Pb−Pb collisions in the toward, away, and transverse regions with the ALICE detector are discussed. These regions are defined event-by-event relative to the azimuthal direction of the charged trigger particle, which is the reconstructed particle with the largest transverse momentum (ptrigT) in the range 8<ptrigT<15 GeV/c. The toward and away regions contain the primary and recoil jets, respectively; both regions are accompanied by the underlying event (UE). In contrast, the transverse region perpendicular to the direction of the trigger particle is dominated by the so-called UE dynamics, and includes also contributions from initial- and final-state radiation. The relative transverse activity classifier, RT=NTch/⟨NTch⟩, is used to group events according to their UE activity, where NTch is the charged-particle multiplicity per event in the transverse region and ⟨NTch⟩ is the mean value over the whole analysed sample. The energy dependence of the RT distributions in pp collisions at s√=2.76, 5.02, 7, and 13 TeV is reported, exploring the Koba-Nielsen-Olesen (KNO) scaling properties of the multiplicity distributions. The first measurements of charged-particle pT spectra as a function of RT in the three azimuthal regions in pp, p−Pb, and Pb−Pb collisions at sNN−−−√=5.02 TeV are also reported. Data are compared with predictions obtained from the event generators PYTHIA 8 and EPOS LHC. This set of measurements is expected to contribute to the understanding of the origin of collective-like effects in small collision systems (pp and p−Pb).
Measurements of charged-particle production in pp, p−Pb, and Pb−Pb collisions in the toward, away, and transverse regions with the ALICE detector are discussed. These regions are defined event-by-event relative to the azimuthal direction of the charged trigger particle, which is the reconstructed particle with the largest transverse momentum (ptrigT) in the range 8<ptrigT<15 GeV/c. The toward and away regions contain the primary and recoil jets, respectively; both regions are accompanied by the underlying event (UE). In contrast, the transverse region perpendicular to the direction of the trigger particle is dominated by the so-called UE dynamics, and includes also contributions from initial- and final-state radiation. The relative transverse activity classifier, RT=NTch/⟨NTch⟩, is used to group events according to their UE activity, where NTch is the charged-particle multiplicity per event in the transverse region and ⟨NTch⟩ is the mean value over the whole analysed sample. The energy dependence of the RT distributions in pp collisions at s√=2.76, 5.02, 7, and 13 TeV is reported, exploring the Koba-Nielsen-Olesen (KNO) scaling properties of the multiplicity distributions. The first measurements of charged-particle pT spectra as a function of RT in the three azimuthal regions in pp, p−Pb, and Pb−Pb collisions at sNN−−−√=5.02 TeV are also reported. Data are compared with predictions obtained from the event generators PYTHIA 8 and EPOS LHC. This set of measurements is expected to contribute to the understanding of the origin of collective-like effects in small collision systems (pp and p−Pb).
The Chiral Magnetic Wave (CMW) phenomenon is essential to provide insights into the strong interaction in QCD, the properties of the quark-gluon plasma, and the topological characteristics of the early universe, offering a deeper understanding of fundamental physics in high-energy collisions. Measurements of the charge-dependent anisotropic flow coefficients are studied in Pb-Pb collisions at center-of-mass energy per nucleon-nucleon collision sNN−−−√= 5.02 TeV to probe the CMW. In particular, the slope of the normalized difference in elliptic (v2) and triangular (v3) flow coefficients of positively and negatively charged particles as a function of their event-wise normalized number difference, is reported for inclusive and identified particles. The slope rNorm3 is found to be larger than zero and to have a magnitude similar to rNorm2, thus pointing to a large background contribution for these measurements. Furthermore, rNorm2 can be described by a blast wave model calculation that incorporates local charge conservation. In addition, using the event shape engineering technique yields a fraction of CMW (fCMW) contribution to this measurement which is compatible with zero. This measurement provides the very first upper limit for fCMW, and in the 10-60% centrality interval it is found to be 26% (38%) at 95% (99.7%) confidence level.
The Chiral Magnetic Wave (CMW) phenomenon is essential to provide insights into the strong interaction in QCD, the properties of the quark-gluon plasma, and the topological characteristics of the early universe, offering a deeper understanding of fundamental physics in high-energy collisions. Measurements of the charge-dependent anisotropic flow coefficients are studied in Pb-Pb collisions at center-of-mass energy per nucleon-nucleon collision sNN−−−√= 5.02 TeV to probe the CMW. In particular, the slope of the normalized difference in elliptic (v2) and triangular (v3) flow coefficients of positively and negatively charged particles as a function of their event-wise normalized number difference, is reported for inclusive and identified particles. The slope rNorm3 is found to be larger than zero and to have a magnitude similar to rNorm2, thus pointing to a large background contribution for these measurements. Furthermore, rNorm2 can be described by a blast wave model calculation that incorporates local charge conservation. In addition, using the event shape engineering technique yields a fraction of CMW (fCMW) contribution to this measurement which is compatible with zero. This measurement provides the very first upper limit for fCMW, and in the 10-60% centrality interval it is found to be 26% (38%) at 95% (99.7%) confidence level.
Long- and short-range correlations for pairs of charged particles are studied via two-particle angular correlations in pp collisions at s√=13 TeV and p−Pb collisions at sNN−−−√=5.02 TeV. The correlation functions are measured as a function of relative azimuthal angle Δφ and pseudorapidity separation Δη for pairs of primary charged particles within the pseudorapidity interval |η|<0.9 and the transverse-momentum interval 1<pT<4 GeV/c. Flow coefficients are extracted for the long-range correlations (1.6<|Δη|<1.8) in various high-multiplicity event classes using the low-multiplicity template fit method. The method is used to subtract the enhanced yield of away-side jet fragments in high-multiplicity events. These results show decreasing flow signals toward lower multiplicity events. Furthermore, the flow coefficients for events with hard probes, such as jets or leading particles, do not exhibit any significant changes compared to those obtained from high-multiplicity events without any specific event selection criteria. The results are compared with hydrodynamic-model calculations, and it is found that a better understanding of the initial conditions is necessary to describe the results, particularly for low-multiplicity events.
Long- and short-range correlations for pairs of charged particles are studied via two-particle angular correlations in pp collisions at √sNN = 13 TeV and p–Pb collisions at √s = 5.02 TeV. The correlation functions are measured as a function of relative azimuthal angle ∆φ and pseudorapidity separation ∆η for pairs of primary charged particles within the pseudorapidity interval |η| < 0.9 and the transverse-momentum interval 1 < pT < 4 GeV/c. Flow coefficients are extracted for the long-range correlations (1.6 < |∆η| < 1.8) in various high-multiplicity event classes using the low-multiplicity template fit method. The method is used to subtract the enhanced yield of away-side jet fragments in high-multiplicity events. These results show decreasing flow signals toward lower multiplicity events. Furthermore, the flow coefficients for events with hard probes, such as jets or leading particles, do not exhibit any significant changes compared to those obtained from high-multiplicity events without any specific event selection criteria. The results are compared with hydrodynamic-model calculations, and it is found that a better understanding of the initial conditions is necessary to describe the results, particularly for low-multiplicity events.