Motifs in SARS-CoV-2 evolution.

We present a novel framework enhancing the prediction of whether novel lineage poses the threat of eventually dominating the viral population. The framework is based purely on genomic sequence data, without requiring prior established biological analysis. Its building blocks are sets of coevolving sites in the alignment (motifs), identified via coevolutionary signals. The collection of such motifs forms a relational structure over the polymorphic sites. Motifs are constructed using distances quantifying the coevolutionary coupling of pairs and manifest as coevolving clusters of sites. We present an approach to genomic surveillance based on this notion of relational structure. Our system will issue an alert regarding a lineage, based on its contribution to drastic changes in the relational structure. We then conduct a comprehensive retrospective analysis of the COVID-19 pandemic based on SARS-CoV-2 genomic sequence data in GISAID from October 2020 to September 2022, across 21 lineages and 27 countries with weekly resolution. We investigate the performance of this surveillance system in terms of its accuracy, timeliness, and robustness. Lastly, we study how well each lineage is classified by such a system.

Photoproduction of K

K^{+}K^{-} pairs may be produced in photonuclear collisions, either from the decays of photoproduced ϕ(1020) mesons or directly as nonresonant K^{+}K^{-} pairs. Measurements of K^{+}K^{-} photoproduction probe the couplings between the ϕ(1020) and charged kaons with photons and nuclear targets. The kaon-proton scattering occurs at energies far above those available elsewhere. We present the first measurement of coherent photoproduction of K^{+}K^{-} pairs on lead ions in ultraperipheral collisions using the ALICE detector, including the first investigation of direct K^{+}K^{-} production. There is significant K^{+}K^{-} production at low transverse momentum, consistent with coherent photoproduction on lead targets. In the mass range 1.1

Emergence of Long-Range Angular Correlations in Low-Multiplicity Proton-Proton Collisions.

This Letter presents the measurement of near-side associated per-trigger yields, denoted ridge yields, from the analysis of angular correlations of charged hadrons in proton-proton collisions at sqrt[s]=13 TeV. Long-range ridge yields are extracted for pairs of charged particles with a pseudorapidity difference of 1.4<|Δη|<1.8 and a transverse momentum of 1

First Measurement of the |t| Dependence of Incoherent J/ψ Photonuclear Production.

The first measurement of the cross section for incoherent photonuclear production of J/ψ vector mesons as a function of the Mandelstam |t| variable is presented. The measurement was carried out with the ALICE detector at midrapidity, |y|<0.8, using ultraperipheral collisions of Pb nuclei at a center-of-mass energy per nucleon pair of sqrt[s_{NN}]=5.02 TeV. This rapidity interval corresponds to a Bjorken-x range (0.3-1.4)×10^{-3}. Cross sections are given in five |t| intervals in the range 0.04<|t|<1 GeV^{2} and compared to the predictions by different models. Models that ignore quantum fluctuations of the gluon density in the colliding hadron predict a |t| dependence of the cross section much steeper than in data. The inclusion of such fluctuations in the same models provides a better description of the data.

ψ(2S) Suppression in Pb-Pb Collisions at the LHC.

The production of the ψ(2S) charmonium state was measured with ALICE in Pb-Pb collisions at sqrt[s_{NN}]=5.02 TeV, in the dimuon decay channel. A significant signal was observed for the first time at LHC energies down to zero transverse momentum, at forward rapidity (2.5

High-Density Lipoproteins at the Interface between the NLRP3 Inflammasome and Myocardial Infarction.

Despite significant therapeutic advancements, morbidity and mortality following myocardial infarction (MI) remain unacceptably high. This clinical challenge is primarily attributed to two significant factors: delayed reperfusion and the myocardial injury resulting from coronary reperfusion. Following reperfusion, there is a rapid intracellular pH shift, disruption of ionic balance, heightened oxidative stress, increased activity of proteolytic enzymes, initiation of inflammatory responses, and activation of several cell death pathways, encompassing apoptosis, necroptosis, and pyroptosis. The inflammatory cell death or pyroptosis encompasses the activation of the intracellular multiprotein complex known as the NLRP3 inflammasome. High-density lipoproteins (HDL) are endogenous particles whose components can either promote or mitigate the activation of the NLRP3 inflammasome. In this comprehensive review, we explore the role of inflammasome activation in the context of MI and provide a detailed analysis of how HDL can modulate this process.

Gene-Environment Interactions in Irrational Beliefs: The Roles of Childhood Adversity and Multiple Candidate Genes.

Cognitive behavioral therapy is based on the view that maladaptive thinking is the causal mechanism of mental disorders. While this view is supported by extensive evidence, very limited work has addressed the factors that contribute to the development of maladaptive thinking. The present study aimed to uncover interactions between childhood maltreatment and multiple genetic differences in irrational beliefs. Childhood maltreatment and irrational beliefs were assessed using multiple self-report instruments in a sample of healthy volunteers (N = 452). Eighteen single-nucleotide polymorphisms were genotyped in six candidate genes related to neurotransmitter function (COMT; SLC6A4; OXTR), neurotrophic factors (BDNF), and the hypothalamic-pituitary-adrenal axis (NR3C1; CRHR1). Gene-environment interactions (G×E) were first explored in models that employed one measure of childhood maltreatment and one measure of irrational beliefs. These effects were then followed up in models in which either the childhood maltreatment measure, the irrational belief measure, or both were substituted by parallel measures. Consistent results across models indicated that childhood maltreatment was positively associated with irrational beliefs, and these relations were significantly influenced by COMT rs165774 and OXTR rs53576. These results remain preliminary until independent replication, but they represent the best available evidence to date on G×E in a fundamental mechanism of psychopathology.

Effect of Empagliflozin with or without the Addition of Evolocumab on HDL Subspecies in Individuals with Type 2 Diabetes Mellitus: A Post Hoc Analysis of the EXCEED-BHS3 Trial.

Evolocumab and empagliflozin yield a modest rise in plasma high-density lipoprotein cholesterol (HDL-C) through unknown mechanisms. This study aims to assess the effect of evolocumab plus empagliflozin vs. empagliflozin alone on HDL subspecies isolated from individuals with type 2 diabetes mellitus (T2D). This post hoc prespecified analysis of the EXCEED-BHS3 trial compared the effects of a 16-week therapy with empagliflozin (E) alone or in combination with evolocumab (EE) on the lipid profile and cholesterol content in HDL subspecies in individuals with T2D divided equally into two groups of 55 patients. Both treatments modestly increased HDL-C. The cholesterol content in HDL subspecies 2a (7.3%), 3a (7.2%) and 3c (15%) increased from baseline in the E group, while the EE group presented an increase from baseline in 3a (9.3%), 3b (16%) and 3c (25%). The increase in HDL 3b and 3c was higher in the EE group when compared to the E group (p < 0.05). No significant interactive association was observed between changes in hematocrit and HDL-C levels after treatment. Over a 16-week period, empagliflozin with or without the addition of evolocumab led to a modest but significant increase in HDL-C. The rise in smaller-sized HDL particles was heterogeneous amongst the treatment combinations.

Serotonin and emotion regulation: the impact of tryptophan depletion on emotional experience, neural and autonomic activity.

The involvement of serotonin in emotion and psychopathology has been extensively examined. Studies using acute tryptophan depletion (ATD) have found limited effects on mood and aggression, and one of the explanations suggests that serotonin may be involved in higher-order functions, such as emotion regulation. However, there is very limited evidence for this hypothesis. The present study investigated the impact of ATD on emotion regulation in a double-blind, placebo-controlled, crossover design. A sample of psychiatrically healthy men (N = 28) completed a cognitive task assessing reappraisal ability (i.e., the success of using reappraisal, an emotion regulation strategy, to modulate emotional responses), following ATD and placebo. EEG frontal activity and asymmetry, as well as heart-rate variability (HRV), also were assessed in the reappraisal task. Both frequentist and Bayesian methods were employed for statistical analysis. Results indicated that ATD reduced plasma tryptophan, and reappraisal was effective in modulating emotional experience in the emotion regulation task. However, ATD had no significant effect on reappraisal ability, frontal activity, and HRV. These results offer direct and compelling evidence that decreasing serotonin synthesis through ATD does not alter an emotion regulation ability that is considered crucial in mood and aggression and has been linked with transdiagnostic risk of psychopathology.

Phenotypic changes in low-density lipoprotein particles as markers of adverse clinical outcomes in COVID-19.

BACKGROUND AND AIMS: Low-density lipoprotein (LDL) plasma concentration decline is a biomarker for acute inflammatory diseases, including coronavirus disease-2019 (COVID-19). Phenotypic changes in LDL during COVID-19 may be equally related to adverse clinical outcomes. METHODS: Individuals hospitalized due to COVID-19 (n = 40) were enrolled. Blood samples were collected on days 0, 2, 4, 6, and 30 (D0, D2, D4, D6, and D30). Oxidized LDL (ox-LDL), and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity were measured. In a consecutive series of cases (n = 13), LDL was isolated by gradient ultracentrifugation from D0 and D6 and was quantified by lipidomic analysis. Association between clinical outcomes and LDL phenotypic changes was investigated. RESULTS: In the first 30 days, 42.5% of participants died due to Covid-19. The serum ox-LDL increased from D0 to D6 (p < 0.005) and decreased at D30. Moreover, individuals who had an ox-LDL increase from D0 to D6 to over the 90th percentile died. The plasma Lp-PLA2 activity also increased progressively from D0 to D30 (p < 0.005), and the change from D0 to D6 in Lp-PLA2 and ox-LDL were positively correlated (r = 0.65, p < 0.0001). An exploratory untargeted lipidomic analysis uncovered 308 individual lipids in isolated LDL particles. Paired-test analysis from D0 and D6 revealed higher concentrations of 32 lipid species during disease progression, mainly represented by lysophosphatidyl choline and phosphatidylinositol. In addition, 69 lipid species were exclusively modulated in the LDL particles from non-survivors as compared to survivors. CONCLUSIONS: Phenotypic changes in LDL particles are associated with disease progression and adverse clinical outcomes in COVID-19 patients and could serve as a potential prognostic biomarker.

Measurement of the J/ψ Polarization with Respect to the Event Plane in Pb-Pb Collisions at the LHC.

We study the polarization of inclusive J/ψ produced in Pb-Pb collisions at sqrt[s_{NN}]=5.02 TeV at the LHC in the dimuon channel, via the measurement of the angular distribution of its decay products. We perform the study in the rapidity region 2.5

Enhanced Deuteron Coalescence Probability in Jets.

The transverse-momentum (p_{T}) spectra and coalescence parameters B_{2} of (anti)deuterons are measured in p-p collisions at sqrt[s]=13 TeV for the first time in and out of jets. In this measurement, the direction of the leading particle with the highest p_{T} in the event (p_{T}^{lead}>5 GeV/c) is used as an approximation for the jet axis. The event is consequently divided into three azimuthal regions, and the jet signal is obtained as the difference between the toward region, that contains jet fragmentation products in addition to the underlying event (UE), and the transverse region, which is dominated by the UE. The coalescence parameter in the jet is found to be approximately a factor of 10 larger than that in the underlying event. This experimental observation is consistent with the coalescence picture and can be attributed to the smaller average phase-space distance between nucleons in the jet cone as compared with the underlying event. The results presented in this Letter are compared to predictions from a simple nucleon coalescence model, where the phase-space distributions of nucleons are generated using pythia8 with the Monash 2013 tuning, and to predictions from a deuteron production model based on ordinary nuclear reactions with parametrized energy-dependent cross sections tuned on data. The latter model is implemented in pythia8.3. Both models reproduce the observed large difference between in-jet and out-of-jet coalescence parameters, although the almost flat trend of the B_{2}^{Jet} is not reproduced by the models, which instead give a decreasing trend.

First Measurement of Antideuteron Number Fluctuations at Energies Available at the Large Hadron Collider.

The first measurement of event-by-event antideuteron number fluctuations in high energy heavy-ion collisions is presented. The measurements are carried out at midrapidity (|η|<0.8) as a function of collision centrality in Pb-Pb collisions at sqrt[s_{NN}]=5.02 TeV using the ALICE detector. A significant negative correlation between the produced antiprotons and antideuterons is observed in all collision centralities. The results are compared with a state-of-the-art coalescence calculation. While it describes the ratio of higher order cumulants of the antideuteron multiplicity distribution, it fails to describe quantitatively the magnitude of the correlation between antiproton and antideuteron production. On the other hand, thermal-statistical model calculations describe all the measured observables within uncertainties only for correlation volumes that are different with respect to those describing proton yields and a similar measurement of net-proton number fluctuations.

Measurement of the Lifetime and Λ Separation Energy of _{Λ}

The most precise measurements to date of the _{Λ}^{3}H lifetime τ and Λ separation energy B_{Λ} are obtained using the data sample of Pb-Pb collisions at sqrt[s_{NN}]=5.02 TeV collected by ALICE at the LHC. The _{Λ}^{3}H is reconstructed via its charged two-body mesonic decay channel (_{Λ}^{3}H→^{3}He+π^{-} and the charge-conjugate process). The measured values τ=[253±11(stat)±6(syst)] ps and B_{Λ}=[102±63(stat)±67(syst)] keV are compatible with predictions from effective field theories and confirm that the _{Λ}^{3}H structure is consistent with a weakly bound system.

Measurements of Groomed-Jet Substructure of Charm Jets Tagged by D

Understanding the role of parton mass and Casimir color factors in the quantum chromodynamics parton shower represents an important step in characterizing the emission properties of heavy quarks. Recent experimental advances in jet substructure techniques have provided the opportunity to isolate and characterize gluon emissions from heavy quarks. In this Letter, the first direct experimental constraint on the charm-quark splitting function is presented, obtained via the measurement of the groomed shared momentum fraction of the first splitting in charm jets, tagged by a reconstructed D^{0} meson. The measurement is made in proton-proton collisions at sqrt[s]=13 TeV, in the low jet transverse-momentum interval of 15≤p_{T}^{jet ch}<30 GeV/c where the emission properties are sensitive to parton mass effects. In addition, the opening angle of the first perturbative emission of the charm quark, as well as the number of perturbative emissions it undergoes, is reported. Comparisons to measurements of an inclusive-jet sample show a steeper splitting function for charm quarks compared with gluons and light quarks. Charm quarks also undergo fewer perturbative emissions in the parton shower, with a reduced probability of large-angle emissions.

Carotid intima layer thickness but not intima-media thickness is related to coronary artery calcification in type 2 diabetes individuals: Results from the Brazilian diabetes study.

BACKGROUND AND AIMS: Carotid intima-media thickness (cIMT) is inconsistent in predicting cardiovascular risk. This may stem from the variability of the media thickness (cM) outweighing the intimal thickness (cIT) as the sign of atherosclerosis. Thus, we evaluated in type 2 diabetes (T2D) individuals, the association between carotid measures and coronary artery calcification (CAC). METHODS AND RESULTS: Association between the presence of CAC and cIT, cM, and cIMT were examined on 224 individuals. Logistic binary regression was used to assess CAC predictors. The Akaike information criterion (AIC) and log-likelihood test (LLT) were used to assess differences among univariate models. The cIT (0.335 mm vs 0.363 mm; p = 0.001) and cIMT (0.715 vs 0.730; p = 0.019), but not cM (0.386 mm vs 0,393 mm; p = 0.089) were higher among individuals with CAC. In unadjusted analysis, cIT (273;-134; p = 0.001) showed greater relationship with CAC, when compared to cIMT (279;-137; p = 0.022) and cM (281;-139; p = 0.112) based on the AIC and LLT, respectively. In multivariate logistic regression, CAC was related to carotid plaque (OR): 1.91, 95% confidence interval (CI):1.08, 3.38; p = 0.027), and high-cIT (OR: 2.70, 95%CI:1.51, 4.84; p = 0.001), but not to high-cIMT (OR:1.70, 95%CI:0.96, 3.00; p = 0.067) nor high-cM (OR:1.33, 95%CI:0.76, 2.34; p = 0.322). CONCLUSION: In T2D individuals, cIT is a better predictor of CAC than cIMT; cM is not associated with CAC.

Effect of open windows on airborne contamination and its topographical distribution in the dental operatory.

Aerosols produced by dental handpieces represent a permanent risk of disease transmission in the dental environment. The current study evaluated the effects of natural ventilation (open windows) on Streptococcus mutans airborne contamination by dental handpieces in simulated clinical conditions. A dental phantom was placed on a dental chair at a standard university dental clinic operatory. An S. mutans suspension was infused into the phantom's mouth while an operator performed standardized dental procedures using low (contra-angle) and high speed (turbine) dental handpieces or an ultrasonic scaler, with windows open or closed. Selective medium Petri dishes were placed in 18 sites of the operatory environment to evaluate contamination topographically. Sites were clustered as: wall, floor, ceiling, dental chair, and cabinet. Contamination was expressed as log10 CFU/cm2 . A linear mixed model analysis was used, nesting the sites within each ventilation and handpiece combination. Open windows significantly reduced contamination. The high-speed handpiece provided the highest contamination, followed by the ultrasonic scaler and the low-speed handpiece. Contamination values were much smaller at the ceiling, and much larger at the chair. Opening windows produced more homogeneous contamination of the operatory compared to closed windows. Natural ventilation during dental procedures decreases contamination and affects its topographical distribution.

The association between adverse childhood events and cluster C personality disorders: A meta-analysis.

INTRODUCTION: Studies suggest that adverse childhood events (ACEs) may contribute to the onset and development of cluster C personality disorders. However, the association between ACEs and these disorders remains unclear in terms of consistency across studies and effect magnitude, as well as generalizability within cluster C. The current meta-analysis aimed to examine the associations between ACEs and cluster C personality disorders based on the available literature. METHODS: Systematic searches were conducted in PubMed, Scopus, Web of Science and PsychInfo. Forty-eight eligible studies were included in the analyses, and pooled effect sizes were estimated both at the level of cluster C and at the level of each specific disorder. Moderation and meta-regression analyses were also conducted. RESULTS: ACEs were consistently associated with overall cluster C, as well as each of the specific disorders in this cluster. Sources of heterogeneity included type of instrument used to assess ACEs (questionnaires > interviews) and type of instrument used to assess the personality disorders (clinical interviews > questionnaires, as well as their combination with interview). The associations between ACEs and all cluster C personality disorders decreased with age. CONCLUSIONS: ACEs are consistently associated with all cluster C personality disorders. Future work could approach the mechanisms underlying this association, preferably using longitudinal designs and considering the potential sources of effect variability identified in the present study.

Understanding the Potential Impact of Different Drug Properties on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Transmission and Disease Burden: A Modelling Analysis.

BACKGROUND: The public health impact of the coronavirus disease 2019 (COVID-19) pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of different treatments, and consequently research and procurement priorities, have not been clear. METHODS: Using a mathematical model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, COVID-19 disease and clinical care, we explore the public-health impact of different potential therapeutics, under a range of scenarios varying healthcare capacity, epidemic trajectories; and drug efficacy in the absence of supportive care. RESULTS: The impact of drugs like dexamethasone (delivered to the most critically-ill in hospital and whose therapeutic benefit is expected to depend on the availability of supportive care such as oxygen and mechanical ventilation) is likely to be limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R = 1.35). Therapeutics for different patient populations (those not in hospital, early in the course of infection) and types of benefit (reducing disease severity or infectiousness, preventing hospitalization) could have much greater benefits, particularly in resource-poor settings facing large epidemics. CONCLUSIONS: Advances in the treatment of COVID-19 to date have been focused on hospitalized-patients and predicated on an assumption of adequate access to supportive care. Therapeutics delivered earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have significant impact, and research into their efficacy and means of delivery should be a priority.

Evolocumab on top of empagliflozin improves endothelial function of individuals with diabetes: randomized active-controlled trial.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve endothelial dysfunction and reduce cardiovascular events in individuals with type 2 diabetes (T2D). Proprotein convertase subtilisin/kexin 9 (PCSK9i) inhibitors reduce cardiovascular events in high-risk patients. Whether the addition of PCSK9i to SGLT2i treatment adds benefits is not known. OBJECTIVES: To assess the PCSK9-i effect on the endothelial function of T2D individuals under treatment with SGLT2-i. METHODS: Individuals with T2D were randomized in a 1:1 ratio to a 16-week treatment with either empagliflozin (E) or empagliflozin plus evolocumab (EE). The primary endpoint was post-treatment change from baseline in flow-mediated dilation (FMD) at 1-min. Secondary outcomes included changes in plasma levels of nitric oxide metabolites and isoprostane. RESULTS: A total of 110 patients were enrolled, the mean age was 58 years, and 71% were men. The median post-treatment change in FMD at 1-min was 2.7% (interquartile range [IQR]: 0.9%) and 0.4% (IQR: 0.9%) in the EE and E groups, respectively (p < 0.001). There was a greater increase in plasma levels of nitrate [5.9 (16.5) vs. 2.6 (11.8); p = 0.001] and nitrite [0.14 (0.72) vs. 0.02 (0.74); p = 0.025] in the EE group than in the E group, respectively. Isoprostane reduction was more pronounced in the EE group when compared to the E group [-1.7 (5.9) vs. -1.1 (5.3); p < 0.001). CONCLUSIONS: In individuals with T2D, the addition of evolocumab on top of empagliflozin improves endothelial function.