Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Production of He-4 and (4) in Pb-Pb collisions at root(NN)-N-S=2.76 TeV at the LHC

Results on the production of He-4 and (4) nuclei in Pb-Pb collisions at root(NN)-N-S = 2.76 TeV in the rapidity range vertical bar y vertical bar <1, using the ALICE detector, are presented in this paper. The rapidity densities corresponding to 0-10% central events are found to be dN/dy4(He) = (0.8 +/- 0.4 (stat) +/- 0.3 (syst)) x 10(-6) and dN/dy4 = (1.1 +/- 0.4 (stat) +/- 0.2 (syst)) x 10(-6), respectively. This is in agreement with the statistical thermal model expectation assuming the same chemical freeze-out temperature (T-chem = 156 MeV) as for light hadrons. The measured ratio of (4)/He-4 is 1.4 +/- 0.8 (stat) +/- 0.5 (syst). (C) 2018 Published by Elsevier B.V.Peer reviewe

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Colombian surgical outcomes study insights on perioperative mortality rate, a main indicator of the lancet commission on global surgery – a prospective cohort studyResearch in context

Summary: Background: Surgical care holds significant importance in healthcare, especially in low and middle-income countries, as at least 50% of the 4.2 million deaths within the initial 30 days following surgery take place in these countries. The Lancet Commission on Global Surgery proposed six indicators to enhance surgical care. In Colombia, studies have been made using secondary data. However, strategies to reduce perioperative mortality have not been implemented. This study aims to describe the fourth indicator, perioperative mortality rate (POMR), with primary data in Colombia. Methods: A multicentre prospective cohort study was conducted across 54 centres (hospitals) in Colombia. Each centre selected a 7-day recruitment period between 05/2022 and 01/2023. Inclusion criteria involved patients over 18 years of age undergoing surgical procedures in operating rooms. Data quality was ensured through a verification guideline and statistical analysis using mixed-effects multilevel modelling with a case mix analysis of mortality by procedure-related, patient-related, and hospital-related conditions. Findings: 3807 patients were included with a median age of 48 (IQR 32–64), 80.3% were classified as ASA I or II, and 27% of the procedures had a low-surgical complexity. Leading procedures were Orthopedics (19.2%) and Gynaecology/Obstetrics (17.7%). According to the Clavien–Dindo scale, postoperative complications were distributed in major complications (11.7%, 10.68–12.76) and any complication (31.6%, 30.09–33.07). POMR stood at 1.9% (1.48–2.37), with elective and emergency surgery mortalities at 0.7% (0.40–1.23) and 3% (2.3–3.89) respectively. Interpretation: The POMR was higher than the ratio reported in previous national studies, even when patients had a low–risk profile and low-complexity procedures. The present research represents significant public health progress with valuable insights for national decision-makers to improve the quality of surgical care. Funding: This work was supported by Universidad del Rosario and Fundación Cardioinfantil-Instituto de Cardiología grant number CTO-057-2021, project-ID IV-FGV017

Energy–energy correlators in charm-tagged jets in proton–proton collisions at s=13\sqrt{s} = 13 TeV

In this letter, we present the first measurement of the energy–energy correlator (EEC) in charm-tagged jets from proton–proton (pp) collisions at $\sqrt{s} = 13$ TeV. EECs probe the structure of QCD radiation, providing a unique test of mass-dependent effects in parton showers involving a charm quark and offering a distinct view into non-perturbative phenomena, including the hadronization process. The EEC is measured for charm-tagged jets and flavor-untagged (inclusive) jets with transverse momenta of $10 < p_{\rm T} < 30$ GeV/$c$, where charm-quark mass effects are significant. We observe a significant suppression of the EEC amplitude in charm jets compared to inclusive ones, consistent with the expected suppression of radiation from massive quarks – a fundamental prediction of QCD. Despite the significant amplitude difference, the observed peak positions of the charm and inclusive-jet EEC are similar, indicating a complex interplay between Casimir factor (differentiating quark and gluon jets), and quark-mass (dead-cone) effects in the QCD parton shower and subsequent hadronization effects. Comparisons with next-to-leading order calculations and various Monte Carlo event generators reveal the sensitivity of this observable to both mass effects in the parton shower and hadronization process. These results provide new constraints on theoretical models of heavy-quark jets and offer insights into the parton-to-hadron transition in QCD.In this letter, we present the first measurement of the energy-energy correlator (EEC) in charm-tagged jets from proton-proton (pp) collisions at $\sqrt{s} = 13$ TeV. EECs probe the structure of QCD radiation, providing a unique test of mass-dependent effects in parton showers involving a charm quark and offering a distinct view into non-perturbative phenomena, including the hadronization process. The EEC is measured for charm-tagged jets and flavor-untagged (inclusive) jets with transverse momenta of $10 < p_{\rm T} < 30$ GeV/$c$, where charm-quark mass effects are significant. We observe a significant suppression of the EEC amplitude in charm jets compared to inclusive ones, consistent with the expected suppression of radiation from massive quarks -- a fundamental prediction of QCD. Despite the significant amplitude difference, the observed peak positions of the charm and inclusive-jet EEC are similar, indicating a complex interplay between Casimir factor (differentiating quark and gluon jets), and quark-mass (dead-cone) effects in the QCD parton shower as well as subsequent hadronization effects. Comparisons with next-to-leading order calculations and various Monte Carlo event generators reveal the sensitivity of this observable to both mass effects in the parton shower and hadronization process. These results provide new constraints on theoretical models of heavy-quark jets and offer insights into the parton-to-hadron transition in QCD

Revealing the microscopic mechanism of deuteron formation at the LHC

The formation of light (anti)nuclei with mass number A of few units (e.g., d, $^3$He, and $^4$He) in high-energy hadronic collisions presents a longstanding mystery in nuclear physics [1, 2]. It is not clear how nuclei bound by a few MeV can emerge in environments characterized by temperatures above 100 MeV [3–5], about 100,000 times hotter than the center of the Sun. Despite extensive studies, this question remained unanswered. The ALICE Collaboration now addresses it with a novel approach using deuteron–pion momentum correlations in proton-proton (pp) collisions at the Large Hadron Collider (LHC). Our results provide model-independent evidence that about 80% of the observed (anti)deuterons are produced in nuclear fusion reactions [6] following the decay of short-lived resonances, such as the $\Delta(1232)$. These findings resolve a crucial gap in our understanding of nucleosynthesis in hadronic collisions. Beyond answering the fundamental question on how nuclei are formed in hadronic collisions, the results can be employed in the modeling of the production of light and heavy nuclei in cosmic rays [7] and dark matter decays [8, 9].The formation of light (anti)nuclei with mass number A of a few units (e.g., d, $^3$He, and $^4$He) in high-energy hadronic collisions presents a longstanding mystery in nuclear physics [1,2]. It is not clear how nuclei bound by a few MeV can emerge in environments characterized by temperatures above 100 MeV [3-5], about 100,000 times hotter than the center of the Sun. Despite extensive studies, this question remained unanswered. The ALICE Collaboration now addresses it with a novel approach using deuteron-pion momentum correlations in proton-proton (pp) collisions at the Large Hadron Collider (LHC). Our results provide model-independent evidence that about 80% of the observed (anti)deuterons are produced in nuclear fusion reactions [6] following the decay of short-lived resonances, such as the $\Delta (1232)$. These findings resolve a crucial gap in our understanding of nucleosynthesis in hadronic collisions. Beyond answering the fundamental question on how nuclei are formed in hadronic collisions, the results can be employed in the modeling of the production of light and heavy nuclei in cosmic rays [7] and dark matter decays [8,9]

First observation of ultra-long-range azimuthal correlations in low multiplicity pp and p–Pb collisions at the LHC

This study presents the first observation of ultra-long-range two-particle azimuthal correlations with pseudorapidity separation of $|\Delta \eta| > 5.0$ in proton–proton (pp) andf $|\Delta \eta| > 6.5$ in proton–lead (p–Pb) collisions at the LHC, down to and below the minimum-bias multiplicity. Two-particle correlation coefficients ($V_{2\Delta}$) are measured after removing non-flow (jets and resonance decays) contributions using the template-fit method across various multiplicity classes, providing novel insights into the origin of long-range correlations in small systems. Comparisons with the 3D-Glauber + MUSIC + UrQMD hydrodynamic model reveal significant discrepancies at low multiplicities, indicating possible dynamics beyond typical hydrodynamic behavior. Initial-state models based on the Color Glass Condensate framework generate only short-range correlations, while PYTHIA simulations implemented with the string-shoving mechanism also fail to describe these ultra-long-range correlations. The results challenge existing paradigms and question the underlying mechanisms in low-multiplicity pp and p–Pb collisions. The findings impose significant constraints on models describing collective phenomena in small collision systems and advance the understanding of origin of long-range correlations at Large Hadron Collider (LHC) energies.This study presents the first observation of ultra-long-range two-particle azimuthal correlations with pseudorapidity separation of ($|\Delta \eta| > 5.0$) in proton-proton (pp) and ($|\Delta \eta| > 6.5$) in proton-lead (p-Pb) collisions at the LHC, down to and below the minimum-bias multiplicity. Two-particle correlation coefficients (${V}_{2\Delta}$) are measured after removing non-flow (jets and resonance decays) contributions using the template-fit method across various multiplicity classes, providing novel insights into the origin of long-range correlations in small systems. Comparisons with the 3D-Glauber + MUSIC + UrQMD hydrodynamic model reveal significant discrepancies at low multiplicities, indicating possible dynamics beyond typical hydrodynamic behavior. Initial-state models based on the Color Glass Condensate framework generate only short-range correlations, while PYTHIA simulations implemented with the string-shoving mechanism also fail to describe these ultra-long-range correlations. The results challenge existing paradigms and question the underlying mechanisms in low-multiplicity pp and p-Pb collisions. The findings impose significant constraints on models describing collective phenomena in small collision systems and advance the understanding of origin of long-range correlations at Large Hadron Collider (LHC) energies

D0^0-meson-tagged jet axes difference in proton-proton collisions at s=5.02\sqrt{s }= 5.02 TeV

Heavy-flavor quarks produced in proton–proton (pp) collisions provide a unique opportunity to investigate the evolution of quark-initiated parton showers from initial hard scatterings to final-state hadrons. By examining jets that contain heavy-flavor hadrons, this study explores the effects of both perturbative and non-perturbative QCD on jet formation and structure. The angular differences between various jet axes, $\Delta R_{\rm axis}$, offer insight into the radiation patterns and fragmentation of charm quarks. The first measurement of D0-tagged jet axes differences in pp collisions at $\sqrt{s} = 5.02$ TeV by the ALICE experiment at the LHC is presented for jets with transverse momentum $p_{\rm T}^{\rm ch \, jet} \ge10$ GeV/$c$ and D$^0$ mesons with $p_{\rm T}^{\rm D^{0}} \ge 5$ GeV/$c$. In this D$^{0}$-meson-tagged jet measurement, three jet axis definitions, each with different sensitivities to soft, wide-angle radiation, are used: the Standard axis, Soft Drop groomed axis, and Winner-Takes-All axis. Measurements of the radial distributions of D$^0$ mesons with respect to the jet axes, $\Delta R_{\rm axis-D^{0}}$, are reported, along with the angle, $\Delta R_{\rm axis}$, between the three jet axes. The D0 meson emerges as the leading particle in these jets, closely aligning with the Winner-Takes-All axis and diverging from the Standard jet axis. The results also examine how varying the sensitivity to soft radiation with grooming influences the orientation of the Soft Drop jet axis, and uncover that charm-jet structure is more likely to survive grooming when the Soft Drop axis is further from the D$^0$ direction, providing further evidence of the dead-cone effect recently measured by ALICE.Heavy-flavor quarks produced in proton-proton (pp) collisions provide a unique opportunity to investigate the evolution of quark-initiated parton showers from initial hard scatterings to final-state hadrons. By examining jets that contain heavy-flavor hadrons, this study explores the effects of both perturbative and non-perturbative QCD on jet formation and structure. The angular differences between various jet axes, $\Delta R_{\rm axis}$, offer insight into the radiation patterns and fragmentation of charm quarks. The first measurement of D$^{0}$-tagged jet axes differences in pp collisions at $\sqrt{s}=5.02$ TeV by the ALICE experiment at the LHC is presented for jets with transverse momentum $p_{\rm T}^{\rm ch~jet} \geq 10$${\rm GeV}/c$ and D$^0$ mesons with $p_{\rm T}^{\rm D^{0}} \geq 5$${\rm GeV}/c$. In this D$^0$-meson-tagged jet measurement, three jet axis definitions, each with different sensitivities to soft, wide-angle radiation, are used: the Standard axis, Soft Drop groomed axis, and Winner-Takes-All axis. Measurements of the radial distributions of D$^0$ mesons with respect to the jet axes, $\Delta R_{\mathrm{axis-D^0}}$, are reported, along with the angle, $\Delta R_{\mathrm{axis}}$, between the three jet axes. The D$^{0}$ meson emerges as the leading particle in these jets, closely aligning with the Winner-Takes-All axis and diverging from the Standard jet axis. The results also examine how varying the sensitivity to soft radiation with grooming influences the orientation of the Soft Drop jet axis, and uncover that charm-jet structure is more likely to survive grooming when the Soft Drop axis is further from the D$^{0}$ direction, providing further evidence of the dead-cone effect recently measured by ALICE

Exploring nuclear structure with multiparticle azimuthal correlations at the LHC

International audienceUnderstanding nuclear structure provides essential insights into the properties of atomic nuclei. In this paper, details of the nuclear structure of $^{\rm 129}$Xe, such as the quadrupole deformation and the nuclear diffuseness, are studied by extensive measurements of anisotropic-flow-related observables in Xe$-$Xe collisions at a center-of-mass energy per nucleon pair $\sqrt{s_{\rm NN}} = 5.44$ TeV with the ALICE detector at the LHC. The results are compared with those from Pb$-$Pb collisions at $\sqrt{s_{\rm NN}} = 5.02$ TeV for a baseline, given that the $^{\rm 208}$Pb nucleus is not deformed. Furthermore, comprehensive comparisons are performed with a state-of-the-art hybrid model using IP-Glasma+MUSIC+UrQMD. It is found that among various IP-Glasma+MUSIC+UrQMD calculations with different values of nuclear parameters, the one using a nuclear diffuseness parameter of $a_0=0.492$ and a nuclear quadrupole deformation parameter of $\beta_2=0.207$ provides a better description of the presented flow measurements. These studies represent an important step towards a thorough exploration of the imaging power of nuclear collisions at ultrarelativistic energy and the search for the imprint of nuclear structure on various flow observables in heavy-ion collisions at the LHC. The findings demonstrate the potential of nuclear structure studies at the TeV energy scale and highlight that the LHC experiments can complement existing low-energy experiments on nuclear structure studies