A Randomized, Controlled Study on the Safety and Efficacy of Maraviroc and/or Favipiravir vs Currently Used Therapy in Severe COVID-19 Adults. “COMVIVIR” Trial.

Multiple studies have established that hyperinflammatory response induced by SARS CoV-2 is a main cause of complications and death in infected subjects. Such dysfunctional immune response has been described as a dysregulated and exacerbated production of cytokines and chemokines that attracts and activates inflammatory cells, which start and sustain pulmonary and systemic damage, thus causing complications that lead to multi organ failure and death. Therefore, we suggest that blocking key inflammation receptors could help to reduce migration and activation of T cells, monocytes/macrophages and neutrophils, thus mitigating the cytokine dysregulation and averting severe complications and death. Importantly, the optimum treatment for COVID-19 severe patients should combine a modulator of the immune response plus a direct antiviral drug against SARS-CoV-2, in order to address both the hyperinflammatory effects of the immune dysregulation and the viral load. Methods: Maraviroc (MVC), a CCR5 antagonist, and Favipiravir (FPV), an antiviral, will be evaluated single and combined, added to the treatment currently used at the Hospital General de México Dr. Eduardo Liceaga for severe COVID-19 patients. One hundred patients will be allocated in four arms [Current treatment only (CT), CT+MVC, CT+FPV, CT+MVC+FPV]. Percentage of patients free of mechanical ventilation or death at day 28, immunophenotyping and viral load will be compared between groups. Discussion: New immune focused therapies are targeting strong inflammation mediators such as IL-6 and IL1-β; nevertheless, to our best knowledge, only one study explores chemotaxis control. The use of a drug therapy that addresses both the regulation of the immune response and the inhibition of viral replication could at the same time, help to alleviate the hyperinflammatory condition and reduce the time of the viral clearance process, therefore improving treatment outcomes

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease

Investigating the nature of the K∗0(700) state with π±K0S correlations at the LHC

The first measurements of femtoscopic correlations with the particle pair combinations π±K0S in pp collisions at s√=13 TeV at the Large Hadron Collider (LHC) are reported by the ALICE experiment. Using the femtoscopic approach, it is shown that it is possible to study the elusive K∗0(700) particle that has been considered a tetraquark candidate for over forty years. Boson source parameters and final-state interaction parameters are extracted by fitting a model assuming a Gaussian source to the experimentally measured two-particle correlation functions. The final-state interaction is modeled through a resonant scattering amplitude, defined in terms of a mass and a coupling parameter, decaying into a π±K0S pair. The extracted mass and Breit-Wigner width, derived from the coupling parameter, of the final-state interaction are found to be consistent with previous measurements of the K∗0(700). The small value and increasing behavior of the correlation strength with increasing source size support the hypothesis that the K∗0(700) is a four-quark state, i.e. a tetraquark state. This latter trend is also confirmed via a simple geometric model that assumes a tetraquark structure of the K∗0(700) resonance

Measurement of the production cross section of prompt Ξ0c baryons in p–Pb collisions at √sNN = 5.02 TeV

The transverse momentum (pT) differential production cross section of the promptly-produced charm-strange baryon Ξ0c (and its charge conjugate Ξ0c¯¯¯¯¯¯) is measured at midrapidity via its hadronic decay into π+Ξ− in p−Pb collisions at a centre-of-mass energy per nucleon−nucleon collision sNN−−−√ = 5.02 TeV with the ALICE detector at the LHC. The Ξ0c nuclear modification factor (RpPb), calculated from the cross sections in pp and p−Pb collisions, is presented and compared with the RpPb of Λ+c baryons. The ratios between the pT-differential production cross section of Ξ0c baryons and those of D0 mesons and Λ+c baryons are also reported and compared with results at forward and backward rapidity from the LHCb Collaboration. The measurements of the production cross section of prompt Ξ0c baryons are compared with a model based on perturbative QCD calculations of charm-quark production cross sections, which includes only cold nuclear matter effects in p−Pb collisions, and underestimates the measurement by a factor of about 50. This discrepancy is reduced when the data is compared with a model in which hadronisation is implemented via quark coalescence. The pT-integrated cross section of prompt Ξ0c-baryon production at midrapidity extrapolated down to pT = 0 is also reported. These measurements offer insights and constraints for theoretical calculations of the hadronisation process. Additionally, they provide inputs for the calculation of the charm production cross section in p−Pb collisions at midrapidity

Measurement of Ω0c baryon production and branching-fraction ratio BR(Ω0c → Ω−e+νe)/BR(Ω0c → Ω−π+) in pp collisions at √s = 13 TeV

The inclusive production of the charm-strange baryon Ω0c is measured for the first time via its semileptonic decay into Ω−e+νe at midrapidity (|y| < 0.8) in proton–proton (pp) collisions at the centre-of-mass energy √s = 13 TeV with the ALICE detector at the LHC. The transverse momentum (pT) differential cross section multiplied by the branching ratio is presented in the interval 2 < pT < 12 GeV/c. The branching-fraction ratio BR(Ω0c → Ω−e+νe)/BR(Ω0c → Ω−π+) is measured to be 1.12 ± 0.22 (stat.) ± 0.27 (syst.). Comparisons with other experimental measurements, as well as with theoretical calculations, are presented

Measurement of the impact-parameter dependent azimuthal anisotropy in coherent ρ0 photoproduction in Pb–Pb collisions at √sNN = 5.02 TeV

The first measurement of the impact-parameter dependent angular anisotropy in the decay of coherently photoproduced ρ0 mesons is presented. The ρ0 mesons are reconstructed through their decay into a pion pair. The measured anisotropy corresponds to the amplitude of the cos(2ϕ) modulation, where ϕ is the angle between the two vectors formed by the sum and the difference of the transverse momenta of the pions, respectively. The measurement was performed by the ALICE Collaboration at the LHC using data from ultraperipheral Pb−Pb collisions at a center-of-mass energy of sNN−−−√ = 5.02 TeV per nucleon pair. Different impact-parameter regions are selected by classifying the events in nuclear-breakup classes. The amplitude of the cos(2ϕ) modulation is found to increase by about one order of magnitude from large to small impact parameters. Theoretical calculations, which describe the measurement, explain the cos(2ϕ) anisotropy as the result of a quantum interference effect at the femtometer scale that arises from the ambiguity as to which of the nuclei is the source of the photon in the interaction

Charged-particle production as a function of the relative transverse activity classifier in pp, p–Pb, and Pb–Pb collisions at the LHC

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)

Multiplicity dependence of charged-particle intra-jet properties in pp collisions at √s = 13 TeV

The first measurement of the multiplicity dependence of intra-jet properties of leading charged-particle jets in proton-proton (pp) collisions is reported. The mean charged-particle multiplicity and jet fragmentation distributions are measured in minimum-bias and high-multiplicity pp collisions at s√ = 13 TeV using the ALICE detector. Jets are reconstructed from charged particles produced in the midrapidity region (|η|<0.9) using the sequential recombination anti-kT algorithm with jet resolution parameters R = 0.2, 0.3, and 0.4 for the transverse momentum (pT) interval 5−110 GeV/c. High-multiplicity events are selected by the forward V0 scintillator detectors. The mean charged-particle multiplicity inside the leading jet cone rises monotonically with increasing jet pT in qualitative agreement with previous measurements at lower energies. The distributions of jet fragmentation functions zch and ξch are measured for different jet-pT intervals. Jet-pT independent fragmentation of leading jets is observed for wider jets except at high- and low-zch. The observed "hump-backed plateau" structure in the ξch distribution indicates suppression of low-pT particles. In high-multiplicity events, an enhancement of the fragmentation probability of low-zch particles accompanied by a suppression of high-zch particles is observed compared to minimum-bias events. This behavior becomes more prominent for low-pT jets with larger jet radius. The results are compared with predictions of QCD-inspired event generators, PYTHIA 8 with Monash 2013 tune and EPOS LHC. It is found that PYTHIA 8 qualitatively reproduces the jet modification in high-multiplicity events except at high jet pT. These measurements provide important constraints to models of jet fragmentation

K∗(892)± resonance production in Pb−Pb collisions at √sNN = 5.02 TeV

The production of K∗(892)± meson resonance is measured at midrapidity (|y|8 GeV/c, consistent with measurements for other light-flavored hadrons. The smallest values are observed in most central collisions, indicating larger energy loss of partons traversing the dense medium