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During 2011 the LHCb experiment at CERN collected 1.0 fb −1 of pp collisions. Due to the large heavy quark production cross-sections, these data provide unprecedented samples of heavy flavoured hadrons. The first results from LHCb have made a significant impact on the flavour physics landscape and have definitively proved the concept of a dedicated experiment in the forward region at a hadron collider. This document discusses the implications of these first measurements on classes of extensions to the Standard Model, bearing in mind the interplay with the results of searches for on-shell production of new particles at ATLAS and CMS. The physics potential of an upgrade to the LHCb detector, which would allow an order of magnitude more data to be collected, is emphasised.

The calibration and performance of the LHCb Calorimeter system in Run 1 and 2 at the LHC are described. After a brief description of the sub-detectors and of their role in the trigger, the calibration methods used for each part of the system are reviewed. The changes which occurred with the increase of beam energy in Run 2 are explained. The performances of the calorimetry for \\(\\gamma\\) and \\(\\pi^0\\) are detailed. A few results from collisions recorded at \\(\\sqrt {s}\\) = 7, 8 and 13 TeV are shown.

Objectives Our aim was twofold. First, to validate Anali scores with and without gadolinium (ANALI Gd and ANALI NoGd ) in primary sclerosing cholangitis (PSC) patients. Second, to compare the ANALIs prognostic ability with the recently-proposed potential functional stricture (PFS). Materials and methods This retrospective study included 123 patients with a mean age of 41.5 years, who underwent gadoxetic acid-enahnced MRI (GA-MRI). Five readers independently evaluated all images for calculation of ANALI Gd and ANALI NoGd scores based upon following criteria: intrahepatic bile duct change severity, hepatic dysmorphia, liver parenchymal heterogeneity, and portal hypertension. In addition, hepatobiliary contrast excretion into first-order bile ducts was evaluated on 20-minute hepatobiliary-phase (HBP) images to assess PFS. Inter- and intrareader agreement were calculated (Fleiss´and Cohen kappas). Kaplan-Meier curves were generated for survival analysis. ANALI NoGd , ANALI Gd , and PFS were correlated with clinical scores, labs and outcomes (Cox regression analysis). Results Inter-reader agreement was almost perfect (ϰ = 0.81) for PFS, but only moderate-(ϰ = 0.55) for binary ANALI NoGd . For binary ANALI Gd , the agreement was slightly better on HBP (ϰ = 0.64) than on arterial-phase (AP) (ϰ = 0.53). Univariate Cox regression showed that outcomes for decompensated cirrhosis, orthotopic liver transplantation or death significantly correlated with PFS (HR (hazard ratio) = 3.15, p  < 0.001), ANALI NoGd (HR = 6.42, p  < 0.001), ANALI Gd HBP (HR = 3.66, p  < 0.001) and ANALI Gd AP (HR = 3.79, p  < 0.001). Multivariate analysis identified the PFS, all three ANALI scores, and Revised Mayo Risk Score as independent risk factors for outcomes (HR 3.12, p  < 0.001; 6.12, p  < 0.001; 3.56, p  < 0.001;3.59, p  < 0.001; and 4.13, p  < 0.001, respectively). Conclusion ANALI NoGd and GA-MRI-derived ANALI scores and PFS could noninvasively predict outcomes in PSC patients. Clinical relevance statement The combined use of Anali scores and the potential functional stricture (PFS), both derived from unenhanced-, and gadoxetic acid enhanced-MRI, could be applied as a diagnostic and prognostic imaging surrogate for counselling and monitoring primary sclerosing cholangitis patients. Key Points Primary sclerosing cholangitis patients require radiological monitoring to assess disease stability and for the presence and type of complications . A contrast-enhanced MRI algorithm based on potential functional stricture and ANALI scores risk-stratified these patients . Unenhanced ANALI score had a high negative predictive value, indicating some primary sclerosing cholangitis patients can undergo non-contrast MRI surveillance . Graphical Abstract

Objective Arterial-phase artifacts are gadoxetic acid (GA)–enhanced MRI’s major drawback, ranging from 5 to 39%. We evaluate the effect of dilution and slow injection of GA using automated fluoroscopic triggering on liver MRI arterial-phase (AP) acquisition timing, artifact frequency, and lesion visibility. Methods and materials Saline-diluted 1:1 GA was injected at 1 ml/s into 1413 patients for 3 T liver MRI. Initially, one senior abdominal radiologist, i.e., principal investigator (PI), assessed all MR exams and compared them to previous and follow-up images, as well as the radiology report on record, determining the standard of reference for lesion detection and characterization. Then, three other readers independently evaluated the AP images for artifact type (truncation (TA), transient severe motion (TSM) or mixed), artifact severity (on a 5-point scale), acquisition timing (on a 4-point scale) and visibility (on a 5-point scale) of hypervascular lesions ≥ 5 mm, selected by the PI. Artifact score ≥ 4 and artifact score ≤ 3 were considered significant and non-significant artifacts, respectively. Results Of the 1413 exams, diagnostic-quality arterial-phase images included 1100 (77.8%) without artifacts, 220 (15.6%) with minimal, and 77 (5.4%) with moderate artifacts. Only 16 exams (1.1%) had significant artifacts, 13 (0.9%) with severe artifacts (score 4), and three (0.2%) non-diagnostic artifacts (score 5). AP acquisition timing was optimal in 1369 (96.8%) exams. Of the 449 AP hypervascular lesions, 432 (96.2%) were detected. Conclusion Combined dilution and slow injection of GA with MR results in well-timed arterial-phase images in 96.8% and a reduction of exams with significant artifacts to 1.1%. Clinical relevance statement Hypervascular lesions, in particular HCC detection, hinge on arterial-phase hyperenhancement, making well-timed, artifact-free arterial-phase images a prerequisite for accurate diagnosis. Saline dilution 1:1, slow injection (1 ml/s), and automated bolus triggering reduce artifacts and optimize acquisition timing. Key Points • There was substantial agreement among the three readers regarding the presence and type of arterial-phase (AP) artifacts, acquisition timing, and lesion visibility. • Impaired AP hypervascular lesion visibility occurred in 17 (3.8%) cases; in eight lesions due to mistiming and in nine lesions due to significant artifacts. • When AP timing was suboptimal, it was too late in 40 exams (3%) and too early in 4 exams (0.2%) of exams.

Transcatheter aortic valve implantation is an established, guideline-endorsed treatment for severe aortic stenosis. Precise sizing of the balloon-expandable Myval transcatheter heart valve (THV) series with the aortic annulus is facilitated by increasing its diameter in 1·5 mm increments, compared with the usual 3 mm increments in valve size. The LANDMARK trial aimed to show non-inferiority of the Myval THV series compared with the contemporary THVs Sapien Series (Edwards Lifesciences, Irvine, CA, USA) or Evolut Series (Medtronic, Minneapolis, MN, USA). In this prospective, multinational, randomised, open-label, non-inferiority trial across 31 hospitals in 16 countries (Germany, France, Sweden, the Netherlands, Italy, Spain, New Zealand, Portugal, Greece, Hungary, Poland, Slovakia, Slovenia, Croatia, Estonia, and Brazil), 768 participants with severe symptomatic native aortic stenosis were randomly assigned (1:1) to the Myval THV or a contemporary THV. Eligibility was primarily decided by the heart team in accordance with 2021 European Society of Cardiology guidelines. As per the criteria of the third Valve Academic Research Consortium, the primary endpoint at 30 days was a composite of all-cause mortality, all stroke, bleeding (types 3 and 4), acute kidney injury (stages 2–4), major vascular complications, moderate or severe prosthetic valve regurgitation, and conduction system disturbances resulting in a permanent pacemaker implantation. Non-inferiority of the study device was tested in the intention-to-treat population using a non-inferiority margin of 10·44% and assuming an event rate of 26·10%. This trial is registered with ClinicalTrials.gov, NCT04275726, and EudraCT, 2020-000137-40, and is closed to new participants. Between Jan 6, 2021, and Dec 5, 2023, 768 participants with severe symptomatic native aortic stenosis were randomly assigned, 384 to the Myval THV and 384 to a contemporary THV. 369 (48%) participants had their sex recorded as female, and 399 (52%) as male. The mean age of participants was 80·0 years (SD 5·7) for those treated with the Myval THV and 80·4 years (5·4) for those treated with a contemporary THV. Median Society of Thoracic Surgeons scores were the same in both groups (Myval 2·6% [IQR 1·7–4·0] vs contemporary 2·6% [1·7–4·0]). The primary endpoint showed non-inferiority of the Myval (25%) compared with contemporary THV (27%), with a risk difference of –2·3% (one-sided upper 95% CI 3·8, pnon-inferiority<0·0001). No significant difference was seen in individual components of the primary composite endpoint. In individuals with severe symptomatic native aortic stenosis, the Myval THV met its primary endpoint at 30 days. Meril Life Sciences.

Glycobiology is an underexplored research area in inflammatory bowel disease (IBD), and glycans are relevant to many etiological mechanisms described in IBD. Alterations in N-glycans attached to the immunoglobulin G (IgG) Fc fragment can affect molecular structure and immunological function. Recent genome-wide association studies reveal pleiotropy between IBD and IgG glycosylation. This study aims to explore IgG glycan changes in ulcerative colitis (UC) and Crohn's disease (CD).MethodsIgG glycome composition in patients with UC (n = 507), CD (n = 287), and controls (n = 320) was analyzed by ultra performance liquid chromatography.ResultsStatistically significant differences in IgG glycome composition between patients with UC or CD, compared with controls, were observed. Both UC and CD were associated with significantly decreased IgG galactosylation (digalactosylation, UC: odds ratio [OR] = 0.71; 95% confidence interval [CI], 0.5–0.9; P = 0.01; CD: OR = 0.41; CI, 0.3–0.6; P = 1.4 × 10−9) and significant decrease in the proportion of sialylated structures in CD (OR = 0.46, CI, 0.3–0.6, P = 8.4 × 10−8). Logistic regression models incorporating measured IgG glycan traits were able to distinguish UC and CD from controls (UC: P = 2.13 × 10−6 and CD: P = 2.20 × 10−16), with receiver–operator characteristic curves demonstrating better performance of the CD model (area under curve [AUC] = 0.77) over the UC model (AUC = 0.72) (P = 0.026). The ratio of the presence to absence of bisecting GlcNAc in monogalactosylated structures was increased in patients with UC undergoing colectomy compared with no colectomy (FDR-adjusted, P = 0.05).ConclusionsThe observed differences indicate significantly increased inflammatory potential of IgG in IBD. Changes in IgG glycosylation may contribute to IBD pathogenesis and could alter monoclonal antibody therapeutic efficacy. IgG glycan profiles have translational potential as IBD biomarkers.

-linked glycosylation of the fragment crystallizable (Fc)-region of immunoglobulin G (IgG) is known to have a large influence on the activity of the antibody, an effect reported to be IgG subclass specific. This situation applies both to humans and mice. The mouse is often used as experimental animal model to study the effects of Fc-glycosylation on IgG effector functions, and results are not uncommonly translated back to the human situation. However, while human IgG Fc-glycosylation has been extensively characterized in both health and disease, this is not the case for mice. To characterize the glycosylation profile of murine IgG-Fc and in addition evaluate the systematic glycosylation differences between mouse strains, sexes, and IgG subclasses, we used nanoliquid chromatography mass spectrometry (nanoLC-MS(/MS)) to look at the subclass-specific IgG Fc-glycopeptides of male and female mice from the strains BALB/c, C57BL/6, CD-1, and Swiss Webster. The structural analysis revealed the presence of predominantly fucosylated, diantennary glycans, with varying amounts of galactosylation and α2,6-sialylation. In addition, we report glycosylation features not previously reported in an Fc-specific way on murine IgG, including monoantennary, hybrid, and high mannose structures, as well as diantennary structures without a core fucose, with a bisecting acetylglucosamine, or with α1,3-galactosylation. Pronounced differences were detected between strains and the IgG subclasses within each strain. Especially the large spread in galactosylation and sialylation levels found between both strains and subclasses may vastly influence IgG effector functions. Mouse strain-based and subclass-specific glycosylation differences should be taken into account when designing and interpreting immunological and glycobiological mouse studies involving IgG effector functions.

Changes in N -glycosylation of plasma proteins are observed in many types of cancer, nevertheless, few studies suggest the exact mechanism involved in aberrant protein glycosylation. Here we studied the impact of DNA methylation on the N -glycome in the secretome of the HepG2 cell line derived from hepatocellular carcinoma (HCC). Since the majority of plasma glycoproteins originate from the liver, the HepG2 cells represent a good model for glycosylation changes in HCC that are detectable in blood, which is an easily accessible analytic material in a clinical setting. Two different concentrations of 5-aza-2′-deoxycytidine (5-aza-2dC) differentially affected global genome methylation and induced different glycan changes. Around twenty percent of 84 glyco-genes analysed changed expression level after the 5-aza-2dC treatment as a result of global genome hypomethylation. A correlation study between the changes in glyco-gene expression and the HepG2 glycosylation profile suggests that the MGAT3 gene might be responsible for the glycan changes consistently induced by both doses of 5-aza-2dC. Core-fucosylated tetra-antennary structures were decreased in quantity likely as a result of hypomethylated MGAT3 gene promoter followed by increased expression of this gene.

The impact of genetic variants (single nucleotide polymorphisms [SNPs]) in the clinical heterogeneity of ulcerative colitis (UC) remains unclear. We showed that patients with UC exhibit a deficiency in MGAT5 glycogene transcription in intestinal T cells associated with a hyperimmune response. Herein, we evaluated whether MGAT5 SNPs might functionally impact on T cells glycosylation and plasma IgG glycome in patients with UC, as well as in UC clinical outcomes. Three selected MGAT5 SNPs (rs3814022, rs4953911, and rs1257220), previously associated with severity of autoimmune disease or with plasma glycome composition in healthy individuals, were functionally evaluated in patients with UC through analysis of MGAT5 mRNA levels in colonic (n = 14) and circulating (n = 24) T cells and through profiling the plasma IgG Fc glycosylation (n = 152). MGAT5 SNPs were genotyped in 931 patients with UC from 2 European cohorts and further associated with patients' prognosis. Targeted next-generation sequencing for MGAT5 coding and regulatory regions was also performed. MGAT5 SNPs were shown to be functionally associated with low transcription levels of MGAT5 in colonic and circulating T cells from patients with UC and with agalactosylation of IgGs, often associated with a proinflammatory phenotype. The SNPs rs3814022 and rs4953911 were further associated with the need of biologics. Next-generation sequencing data further revealed a combination of MGAT5 SNPs that stratify patients with UC according to their severity. Our results revealed that MGAT5 SNPs have a phenotypic impact on T cells glycosylation and in plasma IgG glycome composition associated with UC pathogenesis. MGAT5 SNPs display a tendency in the association with a worse disease course in patients with UC.