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Introduction: Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI.
Methods: We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection.
Results: Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2].[IGFBP7] was significantly superior to all previously described markers of AKI (P <0.002), none of which achieved an AUC >0.72. Furthermore, [TIMP-2].[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2].[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method.
Conclusions: Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI. Trial registration: ClinicalTrials.gov number NCT01209169.
A(syn)-U/T and G(syn)-C+ Hoogsteen (HG) base pairs (bps) are energetically more disfavored relative to Watson–Crick (WC) bps in A-RNA as compared to B-DNA by >1 kcal/mol for reasons that are not fully understood. Here, we used NMR spectroscopy, optical melting experiments, molecular dynamics simulations and modified nucleotides to identify factors that contribute to this destabilization of HG bps in A-RNA. Removing the 2′-hydroxyl at single purine nucleotides in A-RNA duplexes did not stabilize HG bps relative to WC. In contrast, loosening the A-form geometry using a bulge in A-RNA reduced the energy cost of forming HG bps at the flanking sites to B-DNA levels. A structural and thermodynamic analysis of purine-purine HG mismatches reveals that compared to B-DNA, the A-form geometry disfavors syn purines by 1.5–4 kcal/mol due to sugar-backbone rearrangements needed to sterically accommodate the syn base. Based on MD simulations, an additional penalty of 3–4 kcal/mol applies for purine-pyrimidine HG bps due to the higher energetic cost associated with moving the bases to form hydrogen bonds in A-RNA versus B-DNA. These results provide insights into a fundamental difference between A-RNA and B-DNA duplexes with important implications for how they respond to damage and post-transcriptional modifications.
This paper presents the measurements of π±, K±, p and p¯¯¯ transverse momentum (pT) spectra as a function of charged-particle multiplicity density in proton–proton (pp) collisions at s√ = 13 TeV with the ALICE detector at the LHC. Such study allows us to isolate the center-of-mass energy dependence of light-flavour particle production. The measurements reported here cover a pT range from 0.1 to 20 GeV/c and are done in the rapidity interval |y|<0.5. The pT-differential particle ratios exhibit an evolution with multiplicity, similar to that observed in pp collisions at s√ = 7 TeV, which is qualitatively described by some of the hydrodynamical and pQCD-inspired models discussed in this paper. Furthermore, the pT-integrated hadron-to-pion yield ratios measured in pp collisions at two different center-of-mass energies are consistent when compared at similar multiplicities. This also extends to strange and multi-strange hadrons, suggesting that, at LHC energies, particle hadrochemistry scales with particle multiplicity the same way under different collision energies and colliding systems.
The measurement of the azimuthal-correlation function of prompt D mesons with charged particles in pp collisions at s√=5.02 TeV and p–Pb collisions at sNN−−−√=5.02 TeV with the ALICE detector at the LHC is reported. The D0, D+, and D∗+ mesons, together with their charge conjugates, were reconstructed at midrapidity in the transverse momentum interval 3<pT<24 GeV/c and correlated with charged particles having pT>0.3 GeV/c and pseudorapidity |η|<0.8. The properties of the correlation peaks appearing in the near- and away-side regions (for Δφ≈0 and Δφ≈π, respectively) were extracted via a fit to the azimuthal correlation functions. The shape of the correlation functions and the near- and away-side peak features are found to be consistent in pp and p–Pb collisions, showing no modifications due to nuclear effects within uncertainties. The results are compared with predictions from Monte Carlo simulations performed with the PYTHIA, POWHEG+PYTHIA, HERWIG, and EPOS 3 event generators.
The pseudorapidity density of charged particles, dNch/dη, in p–Pb collisions has been measured at a centre-of-mass energy per nucleon–nucleon pair of sNN−−−√ = 8.16 TeV at mid-pseudorapidity for non-single-diffractive events. The results cover 3.6 units of pseudorapidity, |η|<1.8. The dNch/dη value is 19.1±0.7 at |η|<0.5. This quantity divided by ⟨Npart⟩ / 2 is 4.73±0.20, where ⟨Npart⟩is the average number of participating nucleons, is 9.5% higher than the corresponding value for p–Pb collisions at sNN−−−√ = 5.02 TeV. Measurements are compared with models based on different mechanisms for particle production. All models agree within uncertainties with data in the Pb-going side, while HIJING overestimates, showing a symmetric behaviour, and EPOS underestimates the p-going side of the dNch/dη distribution. Saturation-based models reproduce the distributions well for η>−1.3. The dNch/dη is also measured for different centrality estimators, based both on the charged-particle multiplicity and on the energy deposited in the Zero-Degree Calorimeters. A study of the implications of the large multiplicity fluctuations due to the small number of participants for systems like p–Pb in the centrality calculation for multiplicity-based estimators is discussed, demonstrating the advantages of determining the centrality with energy deposited near beam rapidity.
The production rates and the transverse momentum distribution of strange hadrons at mid-rapidity (|y|<0.5) are measured in proton-proton collisions at s√ = 13 TeV as a function of the charged particle multiplicity, using the ALICE detector at the LHC. The production rates of K0S, Λ, Ξ, and Ω increase with the multiplicity faster than what is reported for inclusive charged particles. The increase is found to be more pronounced for hadrons with a larger strangeness content. Possible auto-correlations between the charged particles and the strange hadrons are evaluated by measuring the event-activity with charged particle multiplicity estimators covering different pseudorapidity regions. When comparing to lower energy results, the yields of strange hadrons are found to depend only on the mid-rapidity charged particle multiplicity. Several features of the data are reproduced qualitatively by general purpose QCD Monte Carlo models that take into account the effect of densely-packed QCD strings in high multiplicity collisions. However, none of the tested models reproduce the data quantitatively. This work corroborates and extends the ALICE findings on strangeness production in proton-proton collisions at 7 TeV.
Measurement of the inclusive isolated photon production cross section in pp collisions at √s = 7 TeV
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The production cross section of inclusive isolated photons has been measured by the ALICE experiment at the CERN LHC in pp collisions at a centre-of-momentum energy of s√= 7 TeV. The measurement is performed with the electromagnetic calorimeter EMCal and the central tracking detectors, covering a range of |η|<0.27 in pseudorapidity and a transverse momentum range of 10<pγT<60 GeV/c. The result extends the pT coverage of previously published results of the ATLAS and CMS experiments at the same collision energy to smaller pT. The measurement is compared to next-to-leading order perturbative QCD calculations and to the results from the ATLAS and CMS experiments. All measurements and theory predictions are in agreement with each other.
The measurements of the production of prompt D0, D+, D∗+, and D+s mesons in proton–proton (pp) collisions at s√=5.02 TeV with the ALICE detector at the Large Hadron Collider (LHC) are reported. D mesons were reconstructed at mid-rapidity (|y|<0.5) via their hadronic decay channels D0→K−π+, D+→K−π+π+, D∗+→D0π+→K−π+π+, D+s→ϕπ+→K+K−π+, and their charge conjugates. The production cross sections were measured in the transverse momentum interval 0<pT<36 GeV/c for D0, 1<pT<36 GeV/c for D+ and D∗+, and in 2<pT<24 GeV/c for D+s mesons. Thanks to the higher integrated luminosity, an analysis in finer pT bins with respect to the previous measurements at s√=7 TeV was performed, allowing for a more detailed description of the cross-section pT shape. The measured pT-differential production cross sections are compared to the results at s√=7 TeV and to four different perturbative QCD calculations. Its rapidity dependence is also tested combining the ALICE and LHCb measurements in pp collisions at s√=5.02 TeV. This measurement will allow for a more accurate determination of the nuclear modification factor in p–Pb and Pb–Pb collisions performed at the same nucleon–nucleon centre-of-mass energy.
We present a study of the inclusive charged-particle transverse momentum (pT) spectra as a function of charged-particle multiplicity density at mid-pseudorapidity, dNch/dη, in pp collisions at s√=5.02 and 13 TeV covering the kinematic range |η|<0.8 and 0.15<pT<20 GeV/c. The results are presented for events with at least one charged particle in |η|<1 (INEL>0). The pT spectra are reported for two multiplicity estimators covering different pseudorapidity regions. The pT spectra normalized to that for INEL>0 show little energy dependence. Moreover, the high-pT yields of charged particles increase faster than the charged-particle multiplicity density. The average pT as a function of multiplicity and transverse spherocity is reported for pp collisions at s√=13 TeV. For low- (high-) spherocity events, corresponding to jet-like (isotropic) events, the average pT is higher (smaller) than that measured in INEL>0 pp collisions. Within uncertainties, the functional form of ⟨pT⟩(Nch) is not affected by the spherocity selection. While EPOS LHC gives a good description of many features of data, PYTHIA overestimates the average pT in jet-like events.
The pT-differential non-linear flow modes, v4,22, v5,32, v6,33 and v6,222 for π±, K±, K0S , p + p¯¯¯, Λ + Λ¯¯¯¯ and ϕ-meson have been measured for the first time at sNN−−−√ = 5.02 TeV in Pb-Pb collisions with the ALICE detector at the Large Hadron Collider. The results were obtained with a multi-particle technique, correlating the identified hadrons with reference charged particles from a different pseudorapidity region. These non-linear observables probe the contribution from the second and third order initial spatial anisotropy coefficients to higher flow harmonics. All the characteristic features observed in previous pT-differential anisotropic flow measurements for various particle species are also present in the non-linear flow modes, i.e. increase of magnitude with increasing centrality percentile, mass ordering at low pT and particle type grouping in the intermediate pT range. Hydrodynamical calculations (iEBE-VISHNU) that use different initial conditions and values of shear and bulk viscosity to entropy density ratios are confronted with the data at low transverse momenta. These calculations exhibit a better agreement with the anisotropic flow coefficients than the non-linear flow modes. These observations indicate that non-linear flow modes can provide additional discriminatory power in the study of initial conditions as well as new stringent constraints to hydrodynamical calculations.
Two-particle correlations in high-energy collision experiments enable the extraction of particle source radii by using the Bose-Einstein enhancement of pion production at low relative momentum q ∝ 1/R. It was previously observed that in pp collisions at s√ = 7TeV the average pair transverse momentum kT range of such analyses is limited due to large background correlations which were attributed to mini-jet phenomena. To investigate this further, an event-shape dependent analysis of Bose-Einstein correlations for pion pairs is performed in this work. By categorizing the events by their transverse sphericity ST into spherical (ST > 0:7) and jet-like (ST < 0:3) events a method was developed that allows for the determination of source radii for much larger values of kT for the first time. Spherical events demonstrate little or no background correlations while jet-like events are dominated by them. This observation agrees with the hypothesis of a mini-jet origin of the non-femtoscopic background correlations and gives new insight into the physics interpretation of the kT dependence of the radii. The emission source size in spherical events shows a substantially diminished kT dependence, while jet-like events show indications of a negative trend with respect to kT in the highest multiplicity events. Regarding the emission source shape, the correlation functions for both event sphericity classes show good agreement with an exponential shape, rather than a Gaussian one.
The production of charm jets in proton-proton collisions at a center-of-mass energy of s√=7 TeV was measured with the ALICE detector at the CERN Large Hadron Collider. The measurement is based on a data sample corresponding to a total integrated luminosity of 6.23 nb−1, collected using a minimum-bias trigger. Charm jets are identified by the presence of a D0 meson among their constituents. The D0 mesons are reconstructed from their hadronic decay D0 →K−π+. The D0-meson tagged jets are reconstructed using tracks of charged particles (track-based jets) with the anti-kT algorithm in the jet transverse momentum range 5<pchT,jet< 30 GeV/c and pseudorapidity |ηjet| < 0.5. The fraction of charged jets containing a D0-meson increases with pchT,jet from 0.042 ± 0.004 (stat) ± 0.006 (syst) to 0.080 ± 0.009 (stat) ± 0.008 (syst). The distribution of D0-meson tagged jets as a function of the jet momentum fraction carried by the D0 meson in the direction of the jet axis (zch∥) is reported for two ranges of jet transverse momenta, 5<pchT,jet< 15 GeV/c and 15<pchT,jet< 30 GeV/c in the intervals 0.2<zch∥∥<1.0 and 0.4<zch∥∥<1.0, respectively. The data are compared with results from Monte Carlo event generators (PYTHIA 6, PYTHIA 8 and Herwig 7) and with a Next-to-Leading-Order perturbative Quantum Chromodynamics calculation, obtained with the POWHEG method and interfaced with PYTHIA 6 for the generation of the parton shower, fragmentation, hadronisation and underlying event.
The production yield of prompt D mesons and their elliptic flow coefficient v2 were measured with the Event-Shape Engineering (ESE) technique applied to mid-central (10–30% and 30–50% centrality classes) Pb-Pb collisions at the centre-of-mass energy per nucleon pair sNN−−−√=5.02 TeV, with the ALICE detector at the LHC. The ESE technique allows the classification of events, belonging to the same centrality, according to the azimuthal anisotropy of soft particle production in the collision. The reported measurements give the opportunity to investigate the dynamics of charm quarks in the Quark-Gluon Plasma and provide information on their participation in the collective expansion of the medium. D mesons were reconstructed via their hadronic decays at mid-rapidity, |η| < 0.8, in the transverse momentum interval 1 < pT < 24 GeV/c. The v2 coefficient is found to be sensitive to the event-shape selection confirming a correlation between the D-meson azimuthal anisotropy and the collective expansion of the bulk matter, while the per-event D-meson yields do not show any significant modification within the current uncertainties.
The inclusive J/ψ production in Pb–Pb collisions at the center-of-mass energy per nucleon pair sNN−−−√ = 5.02 TeV, measured with the ALICE detector at the CERN LHC, is reported. The J/ψ meson is reconstructed via the dimuon decay channel at forward rapidity (2.5 < y < 4) down to zero transverse momentum. The suppression of the J/ψ yield in Pb–Pb collisions with respect to binary-scaled pp collisions is quantified by the nuclear modification factor (RAA). The RAA at sNN−−−√ = 5.02 TeV is presented and compared with previous measurements at sNN−−−√ = 2.76 TeV as a function of the centrality of the collision, and of the J/ψ transverse momentum and rapidity. The inclusive J/ψ RAA shows a suppression increasing toward higher transverse momentum, with a steeper dependence for central collisions. The modification of the J/ψ average transverse momentum and average squared transverse momentum is also studied. Comparisons with the results of models based on a transport equation and on statistical hadronization are carried out.
The multiplicity dependence of electron production from heavy-flavour hadron decays as a function of transverse momentum was measured in p-Pb collisions at sNN−−−√ = 5.02 TeV using the ALICE detector at the LHC. The measurement was performed in the centre-of-mass rapidity interval −1.07 < ycms < 0.14 and transverse momentum interval 2 < pT < 16 GeV/c. The multiplicity dependence of the production of electrons from heavy-flavour hadron decays was studied by comparing the pT spectra measured for different multiplicity classes with those measured in pp collisions (QpPb) and in peripheral p-Pb collisions (Qcp). The QpPb results obtained are consistent with unity within uncertainties in the measured pT interval and event classes. This indicates that heavy-flavour decay electron production is consistent with binary scaling and independent of the geometry of the collision system. Additionally, the results suggest that cold nuclear matter effects are negligible within uncertainties, in the production of heavy-flavour decay electrons at midrapidity in p-Pb collisions.
The transverse structure of jets was studied via jet fragmentation transverse momentum (jT) distributions, obtained using two-particle correlations in proton-proton and proton-lead collisions, measured with the ALICE experiment at the LHC. The highest transverse momentum particle in each event is used as the trigger particle and the region 3 < pTt < 15GeV/c is explored in this study. The measured distributions show a clear narrow Gaussian component and a wide non-Gaussian one. Based on Pythia simulations, the narrow component can be related to non-perturbative hadronization and the wide component to quantum chromodynamical splitting. The width of the narrow component shows a weak dependence on the transverse momentum of the trigger particle, in agreement with the expectation of universality of the hadronization process. On the other hand, the width of the wide component shows a rising trend suggesting increased branching for higher transverse momentum. The results obtained in pp collisions at s√=7 TeV and in p–Pb collisions at sNN−−−√=5.02 TeV are compatible within uncertainties and hence no significant cold nuclear matter effects are observed. The results are compared to previous measurements from CCOR and PHENIX as well as to PYTHIA 8 and Herwig 7 simulations.
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.