Beneficial effect of ursodeoxycholic acid in patients with acyl-CoA oxidase 2 (ACOX2) deficiency-associated hypertransaminasemia

Background and aims: A variant (p.Arg225Trp) of peroxisomal acyl-CoA oxidase 2 (ACOX2), involved in bile acid (BA) side-chain shortening, has been associated with unexplained persistent hypertransaminasemia and accumulation of C27-BAs, mainly 3?,7?,12?-trihydroxy-5?-cholestanoic acid (THCA). We aimed to investigate the prevalence of ACOX2 deficiency-associated hypertransaminasemia (ADAH), its response to ursodeoxycholic acid (UDCA), elucidate its pathophysiological mechanism and identify other inborn errors that could cause this alteration. Methods and results: Among 33 patients with unexplained hypertransaminasemia from 11 hospitals and 13 of their relatives, seven individuals with abnormally high C27-BA levels (>50% of total BAs) were identified by high-performance liquid chromatography-mass spectrometry. The p.Arg225Trp variant was found in homozygosity (exon amplification/sequencing) in two patients and three family members. Two additional nonrelated patients were heterozygous carriers of different alleles: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). In patients with ADAH, impaired liver expression of ACOX2, but not ACOX3, was found (immunohistochemistry). Treatment with UDCA normalized aminotransferase levels. Incubation of HuH-7 hepatoma cells with THCA, which was efficiently taken up, but not through BA transporters, increased reactive oxygen species production (flow cytometry), endoplasmic reticulum stress biomarkers (GRP78, CHOP, and XBP1-S/XBP1-U ratio), and BAX? expression (reverse transcription followed by quantitative polymerase chain reaction and immunoblot), whereas cell viability was decreased (tetrazolium salt-based cell viability test). THCA-induced cell toxicity was higher than that of major C24-BAs and was not prevented by UDCA. Fourteen predicted ACOX2 variants were generated (site-directed mutagenesis) and expressed in HuH-7 cells. Functional tests to determine their ability to metabolize THCA identified six with the potential to cause ADAH. Conclusions: Dysfunctional ACOX2 has been found in several patients with unexplained hypertransaminasemia. This condition can be accurately identified by a noninvasive diagnostic strategy based on plasma BA profiling and ACOX2 sequencing. Moreover, UDCA treatment can efficiently attenuate liver damage in these patients.Funding information: This study was supported by the following grants: CIBERehd (EHD15PI05/2016); Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain (PI19/00819 and PI20/00189), co-funded by European Regional Development Fund/European Social Fund, “Investing in your future”; “Junta de Castilla y León” (SA074P20); Fundació Marato TV3 (201916–31); AECC Scientific Foundation (2017/2020), Spain; and “Centro Internacional sobre el Envejecimiento” (OLD-HEPAMARKER, 0348_CIE_6_E), Spain. We also acknowledge support from grants PID2019-111669RBI-100, PID2020-115055RB-I00 from Plan Nacional de I+D funded by the “Agencia Estatal de Investigación” (AEI) and the center grant P50AA011999 Southern California Research Center for ALPD and Cirrhosis funded by NIAAA/NIH, as well as support from AGAUR of the “Generalitat de Catalunya” SGR-2017-1112, European Cooperation in Science & Technology (COST) ACTION CA17112 Prospective European Drug-Induced Liver Injury Network. Marta Alonso-Peña was the recipient of a predoctoral fellowship from “Ministerio de Educación, Cultura y Deporte” (BOE-A-2015-9456; FPU-14/00214) and a Mobility Grant for Short Stays from “Ministerio de Ciencia, Innovación y Universidades” (EST17/00186). Ricardo Espinosa-Escudero is the recipient of a predoctoral fellowship from “Junta de Castilla y León” and “Fondo Social Europeo” (EDU/574/2018). The funding sources were not involved in the research design or preparation of the article

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Colombian consensus recommendations for diagnosis, management and treatment of the infection by SARS-COV-2/ COVID-19 in health care facilities - Recommendations from expert´s group based and informed on evidence

La Asociación Colombiana de Infectología (ACIN) y el Instituto de Evaluación de Nuevas Tecnologías de la Salud (IETS) conformó un grupo de trabajo para desarrollar recomendaciones informadas y basadas en evidencia, por consenso de expertos para la atención, diagnóstico y manejo de casos de Covid 19. Estas guías son dirigidas al personal de salud y buscar dar recomendaciones en los ámbitos de la atención en salud de los casos de Covid-19, en el contexto nacional de Colombia

Beneficial effect of ursodeoxycholic acid in patients with acyl-CoA oxidase 2 (ACOX2) deficiency-associated hypertransaminasemia

A variant (p.Arg225Trp) of peroxisomal acyl-CoA oxidase 2 (ACOX2), involved in bile acid (BA) side-chain shortening, has been associated with unexplained persistent hypertransaminasemia and accumulation of C27-BAs, mainly 3α,7α,12α-trihydroxy-5β-cholestanoic acid (THCA). We aimed to investigate the prevalence of ACOX2 deficiency-associated hypertransaminasemia (ADAH), its response to ursodeoxycholic acid (UDCA), elucidate its pathophysiological mechanism and identify other inborn errors that could cause this alteration. Among 33 patients with unexplained hypertransaminasemia from 11 hospitals and 13 of their relatives, seven individuals with abnormally high C27-BA levels (>50% of total BAs) were identified by high-performance liquid chromatography-mass spectrometry. The p.Arg225Trp variant was found in homozygosity (exon amplification/sequencing) in two patients and three family members. Two additional nonrelated patients were heterozygous carriers of different alleles: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). In patients with ADAH, impaired liver expression of ACOX2, but not ACOX3, was found (immunohistochemistry). Treatment with UDCA normalized aminotransferase levels. Incubation of HuH-7 hepatoma cells with THCA, which was efficiently taken up, but not through BA transporters, increased reactive oxygen species production (flow cytometry), endoplasmic reticulum stress biomarkers (GRP78, CHOP, and XBP1-S/XBP1-U ratio), and BAXα expression (reverse transcription followed by quantitative polymerase chain reaction and immunoblot), whereas cell viability was decreased (tetrazolium salt-based cell viability test). THCA-induced cell toxicity was higher than that of major C24-BAs and was not prevented by UDCA. Fourteen predicted ACOX2 variants were generated (site-directed mutagenesis) and expressed in HuH-7 cells. Functional tests to determine their ability to metabolize THCA identified six with the potential to cause ADAH. Dysfunctional ACOX2 has been found in several patients with unexplained hypertransaminasemia. This condition can be accurately identified by a noninvasive diagnostic strategy based on plasma BA profiling and ACOX2 sequencing. Moreover, UDCA treatment can efficiently attenuate liver damage in these patients

Search for bottom quark associated production of the standard model Higgs boson in final states with leptons in proton-proton collisions at s\sqrt{s} = 13 TeV

International audienceThis Letter presents the first search for bottom quark associated production of the standard model Higgs boson, in final states with leptons. Higgs boson decays to pairs of tau leptons and pairs of leptonically decaying W bosons are considered. The search is performed using data collected from 2016 to 2018 by the CMS experiment in proton-proton collisions at a centre-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 138 fb${-1}$. Upper limits at the 95% confidence level are placed on the signal strength for Higgs boson production in association with bottom quarks; the observed (expected) upper limit is 3.7 (6.1) times the standard model prediction

Search for light long-lived particles decaying to displaced jets in proton-proton collisions at s\sqrt{s} = 13.6 TeV

International audienceA search for light long-lived particles decaying to displaced jets is presented, using a data sample of proton-proton collisions at a center-of-mass energy of 13.6 TeV, corresponding to an integrated luminosity of 34.7 fb$^{-1}$, collected with the CMS detector at the CERN LHC in 2022. Novel trigger, reconstruction, and machine-learning techniques were developed for and employed in this search. After all selections, the observations are consistent with the background predictions. Limits are presented on the branching fraction of the Higgs boson to long-lived particles that subsequently decay to quark pairs or tau lepton pairs. An improvement by up to a factor of 10 is achieved over previous limits for models with long-lived particle masses smaller than 60 GeV and proper decay lengths smaller than 1 m. The first constraints are placed on the fraternal twin Higgs and folded supersymmetry models, where the lower bounds on the top quark partner mass reach up to 350 GeV for the fraternal twin Higgs model and 250 GeV for the folded supersymmetry model

Measurement of the Bs0^0_\mathrm{s}→\to J/ψ\psiKS0^0_\mathrm{S} effective lifetime from proton-proton collisions at s\sqrt{s} = 13 TeV

International audienceThe effective lifetime of the B$^0_\mathrm{s}$ meson in the decay B$^0_\mathrm{s}$$\to$ J/$\psi$K$^0_\mathrm{S}$ is measured using data collected during 2016-2018 with the CMS detector in $\sqrt{s}$ = 13 TeV proton-proton collisions at the LHC, corresponding to an integrated luminosity of 140 fb$^{-1}$. The effective lifetime is determined by performing a two-dimensional unbinned maximum likelihood fit to the B$^0_\mathrm{s}$ meson invariant mass and proper decay time distributions. The resulting value of 1.59 $\pm$ 0.07 (stat) $\pm$ 0.03 (syst) ps is the most precise measurement to date and is in good agreement with the expected value

Measurement of inclusive and differential cross sections of single top quark production in association with a W boson in proton-proton collisions at s\sqrt{s} = 13.6 TeV

International audienceThe first measurement of the inclusive and normalised differential cross sections of single top quark production in association with a W boson in proton-proton collisions at a centre-of-mass energy of 13.6 TeV is presented. The data were recorded with the CMS detector at the LHC in 2022, and correspond to an integrated luminosity of 34.7 fb$^{-1}$. The analysed events contain one muon and one electron in the final state. For the inclusive measurement, multivariate discriminants exploiting the kinematic properties of the events are used to separate the signal from the dominant top quark-antiquark production background. A cross section of 82.3 $\pm$ 2.1 (stat) ${}^{+9.9}_{-9.7}$ (syst) $\pm$ 3.3 (lumi) pb is obtained, consistent with the predictions of the standard model. A fiducial region is defined according to the detector acceptance to perform the differential measurements. The resulting differential distributions are unfolded to particle level and show good agreement with the predictions at next-to-leading order in perturbative quantum chromodynamics

Study of WH production through vector boson scattering and extraction of the relative sign of the W and Z couplings to the Higgs boson in proton-proton collisions at s\sqrt{s} = 13 TeV

A search for the production of a W boson and a Higgs boson through vector boson scattering (VBS) is presented, using CMS data from proton-proton collisions at $\sqrt{s}$ = 13 TeV collected from 2016 to 2018. The integrated luminosity of the data sample is 138 fb$^{-1}$. Selected events must be consistent with the presence of two jets originating from VBS, the leptonic decay of the W boson to an electron or muon, and a Higgs boson decaying into a pair of b quarks, reconstructed as either a single merged jet or two resolved jets. A measurement of the process as predicted by the standard model (SM) is performed alongside a study of beyond-the-SM (BSM) scenarios. The SM analysis sets an observed (expected) 95% confidence level upper limit of 14.3 (9.0) on the ratio of the measured VBS WH cross section to that expected by the SM. The BSM analysis, conducted within the so-called $\kappa$ framework, excludes all scenarios with $\lambda_\mathrm{WZ}$ $\lt$ 0 that are consistent with current measurements, where $\lambda_\mathrm{WZ}$ = $\kappa_\mathrm{W}/\kappa_\mathrm{Z}$ and $\kappa_\mathrm{W}$ and $\kappa_\mathrm{Z}$ are the HWW and HZZ coupling modifiers, respectively. The signficance of the exclusion is beyond 5 standard deviations, and it is consistent with the SM expectation of $\lambda_\mathrm{WZ}$ = 1