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Abstract We present SMEFiT3.0, an updated global SMEFT analysis of Higgs, top quark, and diboson production data from the LHC complemented by electroweak precision observables (EWPOs) from LEP and SLD. We consider recent inclusive and differential measurements from the LHC Run II, alongside with a novel implementation of the EWPOs based on independent calculations of the relevant EFT contributions. We estimate the impact of HL-LHC measurements on the SMEFT parameter space when added on top of SMEFiT3.0, through dedicated projections extrapolating from Run II data. We quantify the significant constraints that measurements from two proposed high-energy circular e + e − colliders, the FCC-ee and the CEPC, would impose on both the SMEFT parameter space and on representative UV-complete models. Our analysis considers projections for the FCC-ee and the CEPC based on the latest running scenarios and includes Z-pole EWPOs, fermion-pair, Higgs, diboson, and top quark production, using optimal observables for both the W + W − and the t t ¯ $$ t\overline{t} $$ channels. The framework presented in this work may be extended to other future colliders and running scenarios, providing timely input to ongoing studies towards future high-energy particle physics facilities.

Abstract We discuss a Bayesian methodology for the solution of the inverse problem underlying the determination of parton distribution functions (PDFs). In our approach, Gaussian processes (GPs) are used to model the PDF prior, while Bayes’ theorem is used in order to determine the posterior distribution of the PDFs given a set of data. We discuss the general formalism, the Bayesian inference at the level of both parameters and hyperparameters, and the simplifications which occur when the observable entering the analysis is linear in the PDF. We benchmark the new methodology in two simple examples for the determination of a single PDF flavor from a set of deep inelastic scattering (DIS) data and from a set of equal-time correlators computed using lattice QCD. We discuss our results, showing how the proposed methodology allows for a well-defined statistical interpretation of the different sources of errors entering the PDF uncertainty, and how results can be validated a posteriori.

Abstract We extend the existing leading (LO), next-to-leading (NLO), and next-to-next-to-leading order (NNLO) NNPDF4.0 sets of parton distribution functions (PDFs) to approximate next-to-next-to-next-to-leading order ( $$\hbox {aN}^3\hbox {LO}$$ aN 3 LO ). We construct an approximation to the $$\hbox {N}^3\hbox {LO}$$ N 3 LO splitting functions that includes all available partial information from both fixed-order computations and from small and large x resummation, and estimate the uncertainty on this approximation by varying the set of basis functions used to construct the approximation. We include known $$\hbox {N}^3\hbox {LO}$$ N 3 LO corrections to deep-inelastic scattering structure functions and extend the FONLL general-mass scheme to $$\mathcal {O}\left( \alpha _s^3\right) $$ O α s 3 accuracy. We determine a set of $$\hbox {aN}^3\hbox {LO}$$ aN 3 LO PDFs by accounting both for the uncertainty on splitting functions due to the incomplete knowledge of $$\hbox {N}^3\hbox {LO}$$ N 3 LO terms, and to the uncertainty related to missing higher corrections (MHOU), estimated by scale variation, through a theory covariance matrix formalism. We assess the perturbative stability of the resulting PDFs, we study the impact of MHOUs on them, and we compare our results to the $$\hbox {aN}^3\hbox {LO}$$ aN 3 LO PDFs from the MSHT group. We examine the phenomenological impact of $$\hbox {aN}^3\hbox {LO}$$ aN 3 LO corrections on parton luminosities at the LHC, and give a first assessment of the impact of $$\hbox {aN}^3\hbox {LO}$$ aN 3 LO PDFs on the Higgs and Drell–Yan total production cross-sections. We find that the $$\hbox {aN}^3\hbox {LO}$$ aN 3 LO NNPDF4.0 PDFs are consistent within uncertainties with their NNLO counterparts, that they improve the description of the global dataset and the perturbative convergence of Higgs and Drell–Yan cross-sections, and that MHOUs on PDFs decrease substantially with the increase of perturbative order.

Abstract We construct a set of parton distribution functions (PDFs), based on the recent NNPDF4.0 PDF set, that also include a photon PDF. The photon PDF is constructed using the LuxQED formalism, while QED evolution accounting for $${\mathcal {O}}\left( \alpha \right) $$ O α , $${\mathcal {O}}\left( \alpha \alpha _s\right) $$ O α α s , and $${\mathcal {O}}\left( \alpha ^2\right) $$ O α 2 corrections is implemented and benchmarked by means of the EKO code. We investigate the impact of QED effects on NNPDF4.0, and compare our results both to our previous NNPDF3.1QED PDF set and to other recent PDF sets that include the photon. We assess the impact of photon-initiated processes and electroweak corrections on a variety of representative LHC processes, and find that they can reach the 5% level in vector boson pair production at large invariant mass.

Abstract We include uncertainties due to missing higher order corrections to QCD computations (MHOU) used in the determination of parton distributions (PDFs) in the recent NNPDF4.0 set of PDFs. We use our previously published methodology, based on the treatment of MHOUs and their full correlations through a theory covariance matrix determined by scale variation, now fully incorporated in the new NNPDF theory pipeline. We assess the impact of the inclusion of MHOUs on the NNPDF4.0 central values and uncertainties, and specifically show that they lead to improved consistency of the PDF determination. PDF uncertainties on physical predictions in the data region are consequently either unchanged or moderately reduced by the inclusion of MHOUs.

Abstract Proton-proton collisions at the LHC generate a high-intensity collimated beam of neutrinos in the forward (beam) direction, characterised by energies of up to several TeV. The recent observation of LHC neutrinos by FASER $$\nu $$ ν and SND@LHC signifies that this previously overlooked particle beam is now available for scientific investigation. Here we quantify the impact that neutrino deep-inelastic scattering (DIS) measurements at the LHC would have on the parton distributions (PDFs) of protons and heavy nuclei. We generate projections for DIS structure functions for FASER $$\nu $$ ν and SND@LHC at Run III, as well as for the FASER $$\nu $$ ν 2, AdvSND, and FLArE experiments to be hosted at the proposed Forward Physics Facility (FPF) operating concurrently with the High-Luminosity LHC (HL-LHC). We determine that up to one million electron-neutrino and muon-neutrino DIS interactions within detector acceptance can be expected by the end of the HL-LHC, covering a kinematic region in x and $$Q^2$$ Q 2 overlapping with that of the Electron-Ion Collider. Including these DIS projections in global (n)PDF analyses, specifically PDF4LHC21, NNPDF4.0, and EPPS21, reveals a significant reduction in PDF uncertainties, in particular for strangeness and the up and down valence PDFs. We show that LHC neutrino data enable improved theoretical predictions for core processes at the HL-LHC, such as Higgs and weak gauge boson production. Our analysis demonstrates that exploiting the LHC neutrino beam effectively provides CERN with a “Neutrino-Ion Collider” without requiring modifications in its accelerator infrastructure.

Abstract We revisit our argument that shows that parton distribution functions (PDFs) in the $$\overline{\textrm{MS}}$$ MS ¯ scheme are non-negative in the perturbative region, with the dual goals of clarifying its theoretical underpinnings and elucidating its domain of validity. We specifically discuss recent results proving that PDFs can turn negative at sufficiently low scale, we clarify quantitatively various aspects of our derivation of positivity in the perturbative region, and we provide an estimate for the scale above which PDF positivity holds.

AbstractAntimicrobial resistance is a global health threat. Among Gram-negative bacteria, resistance to carbapenems, a class of β-lactam antibiotics, is usually a proxy for difficult-to-treat resistance, since carbapenem-resistant organisms are often resistant to many classes of antibiotics. Carbapenem resistance in the Gram-negative pathogen Klebsiella pneumoniae is mostly due to the production of carbapenemases, enzymes able to hydrolyze carbapenems, and K. pneumoniae carbapenemase (KPC)-type enzymes are overall the most prevalent carbapenemases in K. pneumoniae. In the last decade, the management of severe infections due to KPC-producing K. pneumoniae (KPC-Kp) in humans has presented many peculiar challenges to clinicians worldwide. In this perspective, we discuss how the treatment of severe KPC-Kp infections has evolved over the last decades, guided by the accumulating evidence from clinical studies, and how recent advances in diagnostics have allowed to anticipate identification of KPC-Kp in infected patients.KEY MESSAGESIn the last decade, the management of severe infections due to KPC-Kp has presented many peculiar challenges to clinicians worldwideFollowing the introduction in clinical practice of novel β-lactam/β-lactamase inhibitor combinations and novel β-lactams active against KPC-producing bacteria, the management of severe KPC-Kp infections has witnessed a remarkable evolutionTreatment of severe KPC-Kp infections is a highly dynamic process, in which the wise use of novel antimicrobials should be accompanied by a continuous refinement based on evolving clinical evidence and laboratory diagnostics

Abstract The Standard Model Effective Field Theory (SMEFT) provides a robust framework to interpret experimental measurements in the context of new physics scenarios while minimising assumptions on the nature of the underlying UV-complete theory. We present the Python open source SMEFiT framework, designed to carry out parameter inference in the SMEFT within a global analysis of particle physics data. SMEFiT is suitable for inference problems involving a large number of EFT degrees of freedom, without restrictions on their functional dependence in the fitted observables, can include UV-inspired restrictions in the parameter space, and implements arbitrary rotations between operator bases. Posterior distributions are determined from two complementary approaches, Nested Sampling and Monte Carlo optimisation. SMEFiT is released together with documentation, tutorials, and post-analysis reporting tools, and can be used to carry out state-of-the-art EFT fits of Higgs, top quark, and electroweak production data. To illustrate its functionalities, we reproduce the results of the recent ATLAS EFT interpretation of Higgs and electroweak data from Run II and demonstrate how equivalent results are obtained in two different operator bases.

Bacterial resistance to antibiotics (antimicrobial resistance, AMR) is spreading globally among major Gram-positive and Gram-negative bacterial pathogens (including staphylococci, enterococci, Enterobacterales, Pseudomonas aeruginosa and Bacterial resistance to antibiotics (antimicrobial resistance, AMR) is rapidly spreading globally among major Gram-positive and Gram-negative bacterial pathogens (including staphylococci, enterococci, Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii); this phenomenon has a remarkable impact on morbidity, mortality and healthcare-associated costs. Evolution and dissemination of AMR can be counteracted with a combined strategy based on i) antimicrobial stewardship programs aimed at a prudent and appropriate use of antibiotics to improve clinical outcomes and reduce the selective pressure for resistance; and ii) infection prevention and control (IPC) practices, to limit the spread of resistant pathogens within the healthcare settings. In this scenario, the nursing staff plays a pivotal role, since these figures are involved in the enforcement and supervision of IPC bundles (e.g., contact precautions, hand, and environmental hygiene, active surveillance, patient isolation, or cohorting), which are essential to limit the spread of resistant pathogens among different patients.

ABSTRACT: Objectives: Ceftolozane/tazobactam (C/T) is a novel cephalosporin and β-lactamase inhibitor combination with great activity against Pseudomonas aeruginosa. To assess P. aeruginosa susceptibility to C/T, a surveillance study was conducted from October 2018 to March 2019 at the University Hospital ‘Ospedali Riuniti’ in Ancona, Italy. Methods: Minimum inhibitory concentrations (MICs) to C/T were determined by Etest strip. Resistant isolates were characterized by phenotypic (broth microdilution antimicrobial susceptibility testing and modified Carbapenem Inactivation Method [mCIM]) and genotypic (Polymerase Chain Reaction [PCR], Pulsed Field Gel Electrophoresis [PFGE], and whole-genome sequencing [WGS]) methods. Clinical variables of patients infected by C/T-resistant P. aeruginosa were collected from medical records. Results: Fifteen of 317 P. aeruginosa collected showed resistance to C/T (4.7%). Ten strains demonstrated carbapenemase activity by mCIM method, and PCR confirmed that eight strains harbored a blaVIM gene while the other two were positive for blaIMP. Additionally, three isolates carried acquired extended spectrum β-lactamase genes (two isolates carried blaPER and one carried blaGES). Eight strains were strictly related by PFGE and WGS analysis confirmed that they belonged to sequence type (ST)111. The other STs found were ST175 (two isolates), ST235 (two isolates), ST70 (one isolate), ST621 (one isolate), and the new ST3354 (one isolate). Most patients had received previous antibiotic therapies, carried invasive devices, and experienced prolonged hospitalization. Conclusion: This study demonstrated the presence of C/T-resistant P. aeruginosa isolates in a regional hospital carrying a number of resistance mechanisms acquired by different high-risk clones.

Abstract We present an updated determination of nuclear parton distributions (nPDFs) from a global NLO QCD analysis of hard processes in fixed-target lepton-nucleus and proton-nucleus together with collider proton-nucleus experiments. In addition to neutral- and charged-current deep-inelastic and Drell–Yan measurements on nuclear targets, we consider the information provided by the production of electroweak gauge bosons, isolated photons, jet pairs, and charmed mesons in proton-lead collisions at the LHC across centre-of-mass energies of 5.02 TeV (Run I) and 8.16 TeV (Run II). For the first time in a global nPDF analysis, the constraints from these various processes are accounted for both in the nuclear PDFs and in the free-proton PDF baseline. The extensive dataset underlying the nNNPDF3.0 determination, combined with its model-independent parametrisation, reveals strong evidence for nuclear-induced modifications of the partonic structure of heavy nuclei, specifically for the small-x shadowing of gluons and sea quarks, as well as the large-x anti-shadowing of gluons. As a representative phenomenological application, we provide predictions for ultra-high-energy neutrino-nucleon cross-sections, relevant for data interpretation at neutrino observatories. Our results provide key input for ongoing and future experimental programs, from that of heavy-ion collisions in controlled collider environments to the study of high-energy astrophysical processes.

Abstract We present a new set of parton distribution functions (PDFs) based on a fully global dataset and machine learning techniques: NNPDF4.0. We expand the NNPDF3.1 determination with 44 new datasets, mostly from the LHC. We derive a novel methodology through hyperparameter optimization, leading to an efficient fitting algorithm built upon stochastic gradient descent. We use NNLO QCD calculations and account for NLO electroweak corrections and nuclear uncertainties. Theoretical improvements in the PDF description include a systematic implementation of positivity constraints and integrability of sum rules. We validate our methodology by means of closure tests and “future tests” (i.e. tests of backward and forward data compatibility), and assess its stability, specifically upon changes of PDF parametrization basis. We study the internal compatibility of our dataset, and investigate the dependence of results both upon the choice of input dataset and of fitting methodology. We perform a first study of the phenomenological implications of NNPDF4.0 on representative LHC processes. The software framework used to produce NNPDF4.0 is made available as an open-source package together with documentation and examples.

Abstract We discuss the Bayesian approach to the solution of inverse problems and apply the formalism to analyse the closure tests performed by the NNPDF collaboration. Starting from a comparison with the approach that is currently used for the determination of parton distributions (PDFs), we discuss some analytical results that can be obtained for linear problems and use these results as a guidance for more complicated non-linear problems. We show that, in the case of Gaussian distributions, the posterior probability density of the parametrized PDFs is fully determined by the results of the NNPDF fitting procedure. Building on the insight that we obtain from the analytical results, we introduce new estimators to assess the statistical faithfulness of the fit results in closure tests. These estimators are defined in data space, and can be studied analytically using the Bayesian formalism in a linear model in order to clarify their meaning. Finally we present results from a number of closure tests performed with current NNPDF methodologies. These further tests allow us to validate the NNPDF4.0 methodology and provide a quantitative comparison of the NNPDF4.0 and NNPDF3.1 methodologies. As PDFs determinations move into precision territory, the need for a careful validation of the methodology becomes increasingly important: the error bar has become the focal point of contemporary PDFs determinations. In this perspective, theoretical assumptions and other sources of error are best formulated and analysed in the Bayesian framework, which provides an ideal language to address the precision and the accuracy of current fits.

Abstract We present the software framework underlying the NNPDF4.0 global determination of parton distribution functions (PDFs). The code is released under an open source licence and is accompanied by extensive documentation and examples. The code base is composed by a PDF fitting package, tools to handle experimental data and to efficiently compare it to theoretical predictions, and a versatile analysis framework. In addition to ensuring the reproducibility of the NNPDF4.0 (and subsequent) determination, the public release of the NNPDF fitting framework enables a number of phenomenological applications and the production of PDF fits under user-defined data and theory assumptions.

Mutations in outer membrane porins act in synergy with carbapenemase enzymes to increase carbapenem resistance in the important nosocomial pathogen, Klebsiella pneumoniae (KP). A key example is a di-amino acid insertion, Glycine-Aspartate (GD), in the extracellular loop 3 (L3) region of OmpK36 which constricts the pore and restricts entry of carbapenems into the bacterial cell. Here we combined genomic and experimental approaches to characterise the diversity, spread and impact of different L3 insertion types in OmpK36. We identified L3 insertions in 3588 (24.1%) of 14,888 KP genomes with an intact ompK36 gene from a global collection. GD insertions were most common, with a high concentration in the ST258/512 clone that has spread widely in Europe and the Americas. Aspartate (D) and Threonine-Aspartate (TD) insertions were prevalent in genomes from Asia, due in part to acquisitions by KP sequence types ST16 and ST231 and subsequent clonal expansions. By solving the crystal structures of novel OmpK36 variants, we found that the TD insertion causes a pore constriction of 41%, significantly greater than that achieved by GD (10%) or D (8%), resulting in the highest levels of resistance to selected antibiotics. We show that in the absence of antibiotics KP mutants harbouring these L3 insertions exhibit both an in vitro and in vivo competitive disadvantage relative to the isogenic parental strain expressing wild type OmpK36. We propose that this explains the reversion of GD and TD insertions observed at low frequency among KP genomes. Finally, we demonstrate that strains expressing L3 insertions remain susceptible to drugs targeting carbapenemase-producing KP, including novel beta lactam-beta lactamase inhibitor combinations. This study provides a contemporary global view of OmpK36-mediated resistance mechanisms in KP, integrating surveillance and experimental data to guide treatment and drug development strategies.

Abstract Rapid detection of carbapenemases as a cause of resistance is beneficial for infection control and antimicrobial therapy. The BD Phoenix NMIC-502 panel and CPO detect test identifies presence of carbapenemases in Enterobacterales such as Klebsiella pneumoniae and assigns them to Ambler classes. To evaluate the performance of the CPO detect panel, we employed a European collection of 1222 K. pneumoniae including carbapenem non-susceptible and susceptible clinical isolates from 26 countries, for which draft genomes were available after Illumina sequencing and the presence of carbapenemase genes had been identified by ARIBA gene calling. The CPO panel detected 488 out of 494 carbapenemase-encoding isolates as positive and six as negative. One-hundred and two isolates were tested positive for carbapenemase in the absence of any carbapenemase gene. The CPO panel identified 229 out of 230 KPC-positive isolates as carbapenemase producing and classified 62 of these as class A enzyme. Similarly, the CPO panel correctly specified 167 of 182 as class D. Regarding metallo-beta-lactamases, the CPO panel assigned 78 of 90 MBL positive isolates to class B enzymes. The sensitivity of the CPO panel in detecting carbapenemase activity was 99.5%, 97.7% and 98.3% for class A, B and D enzymes, respectively. The sensitivity in assignation to Ambler class A, B and D was 27%, 86% and 91%, respectively. An overall sensitivity of 98.8% and specificity of 86% in unclassified detection of carbapenemases was observed, with frequent false positive detection of carbapenemase producing organisms, thus rendering further confirmatory tests necessary.

Background: the aim of this study was to evaluate the performance of the Liquid Colony™ (LC) generated directly from positive blood cultures (PBCs) by the FAST System (Qvella, Richmond Hill, ON, Canada) for rapid identification (ID) and antimicrobial susceptibility testing (AST) compared with the standard of care (SOC) workflow. Methods: Anonymized PBCs were processed in parallel by the FAST System and FAST PBC Prep cartridge (35 min runtime) and SOC. ID was performed by MALDI-ToF mass spectrometry (Bruker, Billerica, MA, USA). AST was performed by reference broth microdilution (Merlin Diagnostika, Bornheim, Germany). Carbapenemase detection was carried out with the lateral flow immunochromatographic assay (LFIA) RESIST-5 O.O.K.N.V. (Coris, Gembloux, Belgium). Polymicrobial PBCs and samples containing yeast were excluded. Results: 241 PBCs were evaluated. ID results showed 100% genus-level concordance and 97.8% species-level concordance between LC and SOC. The AST results for Gram-negative bacteria showed a categorical agreement (CA) of 99.1% (1578/1593), with minor error (mE), major error (ME), and very major error (VME) rates of 0.6% (10/1593), 0.3% (3/1122), and 0.4% (2/471), respectively. The results from Gram-positive bacteria showed a CA of 99.6% (1655/1662), with mE, ME, and VME rates of 0.3% (5/1662), 0.2% (2/1279), and 0.0% (0/378), respectively. Bias evaluation revealed acceptable results for both Gram-negatives and Gram-positives (−12.4% and −6.5%, respectively). The LC yielded the detection of 14/18 carbapenemase producers by LFIA. In terms of turnaround time, the ID, AST, and carbapenemase detection results were generally obtained one day earlier with the FAST System compared with the SOC workflow. Conclusions: The ID, AST, and carbapenemase detection results generated with the FAST System LC were highly concordant with the conventional workflow. The LC allowed species ID and carbapenemase detection within around 1 h after blood culture positivity and AST results within approximately 24 h, which is a significant reduction in the turnaround time of the PBC workflow.

Abstract We extract two nonsinglet nucleon Parton Distribution Functions from lattice QCD data for reduced Ioffe-time pseudodistributions. We perform such analysis within the NNPDF framework, considering data coming from different lattice ensembles and dis- cussing in detail the treatment of the different source of systematics involved in the fit. We introduce a recipe for taking care of systematics and use it to perform our extraction of light-cone PDFs.

Abstract We review recent theoretical developments concerning the definition and the renormalization of equal-time correlators that can be computed on the lattice and related to Parton Distribution Functions (PDFs) through a factorization formula. We show how these objects can be studied and analyzed within the framework of a nongauge theory, gaining insight through a one-loop computation. We use scalar field theory as a playground to revise, analyze and present the main features of these ideas, to explore their potential, and to understand their limitations for extracting PDFs. We then propose a framework that would allow to include the available lattice QCD data in a global analysis to extract PDFs.

Abstract We present a systematic investigation of jet production at hadron colliders from a phenomenological point of view, with the dual aim of providing a validation of theoretical calculations and guidance to future determinations of parton distributions (PDFs). We account for all available inclusive jet and dijet production measurements from ATLAS and CMS at 7 and 8 TeV by including them in a global PDF determination, and comparing to theoretical predictions at NNLO QCD supplemented by electroweak (EW) corrections. We assess the compatibility of the PDFs, specifically the gluon, obtained before and after inclusion of the jet data. We compare the single-inclusive jet and dijet observables in terms of perturbative behaviour upon inclusion of QCD and EW corrections, impact on the PDFs, and global fit quality. In the single-inclusive case, we also investigate the role played by different scale choices and the stability of the results upon changes in modelling of the correlated experimental systematics.

Summary: Background: Carbapenemase-producing Enterobacterales (CPE), particularly those producing metallo-β-lactamases, are among the most challenging antibiotic-resistant pathogens, causing outbreaks of difficult-to-treat nosocomial infections worldwide. Since November 2018, an outbreak of New Delhi metallo-β-lactamases-positive CPE (NDM-CPE) has emerged in Tuscany, Italy. In this study, we aimed to investigate the NDM-CPE associated with the outbreak and characterise the responsible Klebsiella pneumoniae clone. Methods: We used whole-genome sequencing and bioinformatic analysis to characterise NDM-CPE isolates that caused bloodstream infections in 53 patients at 11 hospitals in Tuscany and that were collected between Jan 1, 2018, and July 5, 2019 (ie, the early phase of the outbreak and preceding months). The CPE isolates characterised in this study were isolated and identified at the species level and as NDM producers by six diagnostic microbiology laboratories that serve the 11 hospitals. We used comparative genomic analysis, antimicrobial susceptibility testing, plasmid conjugal transfer assays, evaluation of virulence potential in the Galleria mellonella infection model, and serum bactericidal assays to further characterise the clone causing the outbreak. Findings: The outbreak was sustained by an ST147 K pneumoniae producing NDM-1, which had a complex resistome that mediated resistance to most antimicrobials (except cefiderocol, the aztreonam–avibactam combination, colistin, and fosfomycin). The clone belonged to a sublineage of probably recent evolution, occurred by the sequential acquisition of an integrative and conjugative element encoding the yersiniabactin siderophore, an FIB(pQil)-type multiresistance plasmid carrying blaNDM-1, and a transferable chimeric plasmid, derived from virulence elements of hypervirulent K pneumoniae, carrying several resistance and virulence determinants. Infection of G mellonella larvae revealed a variable virulence potential. The behaviour in serum bactericidal assays was different from typical hypervirulent K pneumoniae strains, with variable grades of serum resistance apparently associated with mutations in specific chromosomal loci (csrD, pal, and ramR). Interpretation: This description of a sublineage of ST147 K pneumoniae with a complex resistome and virulome that is capable of sustaining a large regional outbreak adds to existing research on the evolutionary trajectories within high-risk clones of K pneumoniae. Global surveillance programmes are warranted to track the dissemination of these lineages, and to prevent and control their spread. Funding: Italian Ministry of Health and Department of Experimental and Clinical Medicine, University of Florence.

Antimicrobial resistance and multidrug-resistant organisms currently constitute a severe public health problem [...]

Abstract We formulate a general approach to the inclusion of theoretical uncertainties, specifically those related to the missing higher order uncertainty (MHOU), in the determination of parton distribution functions (PDFs). We demonstrate how, under quite generic assumptions, theory uncertainties can be included as an extra contribution to the covariance matrix when determining PDFs from data. We then review, clarify, and systematize the use of renormalization and factorization scale variations as a means to estimate MHOUs consistently in deep inelastic and hadronic processes. We define a set of prescriptions for constructing a theory covariance matrix using scale variations, which can be used in global fits of data from a wide range of different processes, based on choosing a set of independent scale variations suitably correlated within and across processes. We set up an algebraic framework for the choice and validation of an optimal prescription by comparing the estimate of MHOU encoded in the next-to-leading order (NLO) theory covariance matrix to the observed shifts between NLO and NNLO predictions. We perform a NLO PDF determination which includes the MHOU, assess the impact of the inclusion of MHOUs on the PDF central values and uncertainties, and validate the results by comparison to the known shift between NLO and NNLO PDFs. We finally study the impact of the inclusion of MHOUs in a global PDF determination on LHC cross-sections, and provide guidelines for their use in precision phenomenology. In addition, we also compare the results based on the theory covariance matrix formalism to those obtained by performing PDF determinations based on different scale choices.

Abstract We revise the relation between Parton Distribution Functions (PDFs) and matrix elements computable from lattice QCD, focusing on the quasi-Parton Distribution Functions (qPDFs) approach. We exploit the relation between PDFs and qPDFs in the case of the unpolarized isovector parton distribution to obtain a factorization formula relating the real and imaginary part of qPDFs matrix elements to specific nonsinglet distributions, and we propose a general framework to extract PDFs from the available lattice data, treating them on the same footing as experimental data. We implement the proposed approach within the NNPDF framework, and we study the potentiality of such lattice data in constraining PDFs, assuming some plausible scenarios to assess the unknown systematic uncertainties. We finally extract the two nonsinglet distributions involved in our analysis from a selection of the available lattice data.

Abstract The parton distribution functions (PDFs) which characterize the structure of the proton are currently one of the dominant sources of uncertainty in the predictions for most processes measured at the Large Hadron Collider (LHC). Here we present the first extraction of the proton PDFs that accounts for the missing higher order uncertainty (MHOU) in the fixed-order QCD calculations used in PDF determinations. We demonstrate that the MHOU can be included as a contribution to the covariance matrix used for the PDF fit, and then introduce prescriptions for the computation of this covariance matrix using scale variations. We validate our results at next-to-leading order (NLO) by comparison to the known next order (NNLO) corrections. We then construct variants of the NNPDF3.1 NLO PDF set that include the effect of the MHOU, and assess their impact on the central values and uncertainties of the resulting PDFs.

Abstract We show that a simple and accurate approach to the computation of hadron collider processes involving initial-state b quarks can be obtained by introducing an independently parametrized b PDF. We use the so-called FONLL method for the matching of a scheme in which the b quark is treated as a massless parton to that in which it is treated as a massive state, and extend it to the case in which the b quark PDF is not necessarily determined by perturbative matching conditions. This generalizes to hadronic collisions analogous results previously obtained for deep-inelastic scattering. The results corresponds to a “massive b” scheme, in which b mass effects are retained, yet the b quark is endowed with a PDF. We specifically study Higgs production in bottom fusion, and show that our approach overcomes difficulties related to the fact that in a standard massive four-flavor scheme b-quark induced processes only start at high perturbative orders.

Multidrug resistance (MDR) represents a serious global threat due to the rapid global spread and limited antimicrobial options for treatment of difficult-to-treat (DTR) infections sustained by MDR pathogens. Recently, novel β-lactams/β-lactamase inhibitor combinations (βL-βLICs) have been developed for the treatment of DTR infections due to MDR Gram-negative pathogens. Although novel βL-βLICs exhibited promising in vitro and in vivo activities against MDR pathogens, emerging resistances to these novel molecules have recently been reported. Resistance to novel βL-βLICs is due to several mechanisms including porin deficiencies, increasing carbapenemase expression and/or enzyme mutations. In this review, we summarized the main mechanisms related to the resistance to ceftazidime/avibactam, meropenem/vaborbactam and imipenem/relebactam in MDR Gram-negative micro-organisms. We focused on antimicrobial activities and resistance traits with particular regard to molecular mechanisms related to resistance to novel βL-βLICs. Lastly, we described and discussed the main detection methods for antimicrobial susceptibility testing of such molecules. With increasing reports of resistance to novel βL-βLICs, continuous attention should be maintained on the monitoring of the phenotypic traits of MDR pathogens, into the characterization of related mechanisms, and on the emergence of cross-resistance to these novel antimicrobials.

Hypervirulent Klebsiella pneumoniae (Hv-Kp) strains have emerged as pathogens causing life-threatening, invasive disease even in immunocompetent hosts. Systemic dissemination usually occurs following perturbations of the gut microbiota and is facilitated by Hv-Kp resistance to phagocytosis and complement activity. Hv-Kp are usually associated with K1 or K2 capsular types, produce several iron uptake systems (e.g., aerobactin and salmochelin) and are often but not invariably, capsular material hyper-producers (hypermucoviscous phenotype: HMV). Whether Hv-Kp escape the immune response at mucosal site is unknown. In this work, we studied the effects of Hv-Kp on human dendritic cells (DCs), central players of the IL-23/IL-17 and IL-12/IFN-γ axis at mucosal sites, essential for pathogen clearance. Four Hv-Kp and HMV strains were selected and their activity on DC maturation and cytokine production was compared to that of non-virulent Kp strains with classic or HMV phenotypes. While the maturation process was equally induced by all Kp strains, significant differences between virulent and non-virulent strains were found in the expression of genes for cytokines involved in T-cell activation and differentiation. The non-virulent KP04C62 and the classic Kp, KPC157 induced high expression of TH1 (IL-12p70 and TNFα) and TH17 cytokines (IL-23, IL-1β and IL-6), while Hv-Kp poorly activated these cytokine genes. Moreover, conditioned media from DCs cultured with non-virulent Kp, either classical or hypercapsulated, induced the activation of IL-17 and IFN-γ genes in preactivated CD4+-cells suggesting their TH17/TH1 differentiation. Conditioned media from Hv-Kp poorly activated IL-17 and IFN-γ genes. In summary, our data indicate that Hv-Kp interfere with DC functions and T-cell differentiation and suggest that the escape from the IL-23/IL-17 and IL-12/IFN-γ axes may contribute to pathogen dissemination in immunocompetent hosts.

Abstract We investigated the colistin resistance mechanism in an Escherichia coli strain (LC711/14) isolated in Italy in 2014, from an urinary tract infection, which was previously shown to express a colistin resistance mechanism different from mcr-1. LC711/14 was found to carry a novel mutation in the pmrB gene, resulting in a leucine to proline amino acid substitution at position 10 of the PmrB sensor kinase component of the PmrAB signal transduction system. The role of this substitution in colistin resistance was documented by expression of the wild-type and mutated alleles in a pmrB deletion derivative of the E. coli reference strain MG1655, in which expression of the mutated allele conferred colistin resistance and upregulation of the endogenous pmrHFIJKLM lipid A modification system. Complementation of LC711/14 with the wild-type pmrB allele restored colistin susceptibility and decreased expression of pmrHFIJKLM, confirming the role of this PmrB mutation. Substitution of leucine at position 10 of PmrB with other amino acids (glycine and glutamine) resulted in loss of function, underscoring a key role of this residue which is located in the cytoplasmic secretion domain of the protein. This work demonstrated that mutation in this domain of the PmrB sensor kinase can be responsible for acquired colistin resistance in E. coli strains of clinical origin.

Acquisition of metallo-β-lactamases (MBLs) represents one of most relevant resistance mechanisms to all β-lactams, including carbapenems, ceftolozane and available β-lactamase inhibitors, in Pseudomonas spp. VIM-type enzymes are the most common acquired MBLs in Pseudomonas aeruginosa and, to a lesser extent, in other Pseudomonas species. Little is known about the acquisition dynamics of these determinants, that are usually carried on integrons embedded into chromosomal mobile genetic elements. To date, few MBL-encoding plasmids have been described in Pseudomonas spp., and their diversity and role in the dissemination of these MBLs remains largely unknown. Here we report on the genetic features of the VIM-1-encoding plasmid pMOS94 from P. mosselii AM/94, the earliest known VIM-1-producing strain, and of related elements involved in dissemination of MBL. Results of plasmid DNA sequencing showed that pMOS94 had a modular organization, consisting of backbone modules associated with replication, transfer and antibiotic resistance. Plasmid pMOS94, although not typable according to the PBRT scheme, was classifiable either in MOBF11 or MPFT plasmid families. The resistance region included the class I integron In70, carrying blaV IM-1, in turn embedded in a defective Tn402-like transposon. Comparison with pMOS94-like elements led to the identification of a defined plasmid lineage circulating in different Pseudomonas spp. of clinical and environmental origin and spreading different MBL-encoding genes, including blaIMP-63, blaBIM, and blaV IM-type determinants. Genetic analysis revealed that this plasmid lineage likely shared a common ancestor and had evolved through the acquisition and recombination of different mobile elements, including the MBL-encoding transposons. Our findings provide new insights about the genetic diversity of MBL-encoding plasmids circulating among Pseudomonas spp., potentially useful for molecular epidemiology purposes, and revealed the existence and persistence of a successful plasmid lineage over a wide spatio-temporal interval, spanning over five different countries among two continents and over 20-years.

Objectives: Information is lacking on the methicillin-resistant Staphylococcus aureus (MRSA) clonal lineages circulating in Bolivia. We investigated the prevalence and molecular epidemiology of S. aureus colonization in hospitalized patients from the Bolivian Chaco, and compared their features with those of the few clinical isolates available from that setting. Methods: S. aureus nasal/inguinal colonization was investigated in 280 inpatients from eight hospitals in two point prevalence surveys (2012, n = 90; 2013, n = 190). Molecular characterization included genotyping (spa typing, multilocus sequence typing, and pulsed-field gel electrophoresis), detection of virulence genes, and SCCmec typing. Results: Forty-one inpatients (14.6%) were S. aureus nasal/inguinal carriers, of whom five were colonized by MRSA (1.8%). MRSA isolates mostly belonged to spa-type t701, harboured SCCmec IVc, and were negative for Panton–Valentine leukocidin (PVL) genes. However, a USA300-related isolate was also detected, which showed the characteristics of the USA300 Latin American variant (USA300-LV; i.e., ST8, spa-type t008, SCCmec IVc, presence of PVL genes, absence of arcA). Notably, all the available MRSA clinical isolates (n = 5, collected during 2011–2013) were also identified as USA300-LV. Conclusions: Overall, MRSA colonization in inpatients from the Bolivian Chaco was low. However, USA300-LV-related isolates were detected in colonization and infections, emphasizing the importance of implementing control measures to limit their further dissemination in this resource-limited area.

ABSTRACT The continued rise and spread of antimicrobial resistance among bacterial pathogens pose a serious challenge to global health. Countering antimicrobial-resistant pathogens requires a multifaceted effort that includes the discovery of novel therapeutic approaches. Here, we establish the capacity of the human CXC chemokines CXCL9 and CXCL10 to kill multidrug-resistant Gram-negative bacteria, including New Delhi metallo-beta-lactamase-1-producing Klebsiella pneumoniae and colistin-resistant members of the family Enterobacteriaceae that harbor the mobile colistin resistance protein MCR-1 and thus possess phosphoethanolamine-modified lipid A. Colistin-resistant K. pneumoniae isolates affected by genetic mutation of the PmrA/PmrB two-component system, a chromosomally encoded regulator of lipopolysaccharide modification, and containing 4-amino-4-deoxy-l-arabinose-modified lipid A were also found to be susceptible to chemokine-mediated antimicrobial activity. However, loss of PhoP/PhoQ autoregulatory control, caused by disruption of the gene encoding the negative regulator MgrB, limited the bactericidal effects of CXCL9 and CXCL10 in a variable, strain-specific manner. Cumulatively, these findings provide mechanistic insight into chemokine-mediated antimicrobial activity, highlight disparities amongst determinants of colistin resistance, and suggest that chemokine-mediated bactericidal effects merit additional investigation as a therapeutic avenue for treating infections caused by multidrug-resistant pathogens. IMPORTANCE As bacterial pathogens become resistant to multiple antibiotics, the infections they cause become increasingly difficult to treat. Carbapenem antibiotics provide an essential clinical barrier against multidrug-resistant bacteria; however, the dissemination of bacterial enzymes capable of inactivating carbapenems threatens the utility of these important antibiotics. Compounding this concern is the global spread of bacteria invulnerable to colistin, a polymyxin antibiotic considered to be a last line of defense against carbapenem-resistant pathogens. As the effectiveness of existing antibiotics erodes, it is critical to develop innovative antimicrobial therapies. To this end, we demonstrate that the chemokines CXCL9 and CXCL10 kill the most concerning carbapenem- and colistin-resistant pathogens. Our findings provide a unique and timely foundation for therapeutic strategies capable of countering antibiotic-resistant “superbugs.”

Strains of Klebsiella pneumoniae producing KPC-type beta-lactamases (KPC-Kp) are broadly disseminating worldwide and constitute a major healthcare threat given their extensively drug resistant phenotypes and ability to rapidly disseminate in healthcare settings. In this work we report on the characterization of two different capsular polysaccharide (CPS) gene clusters, named cpsBO-4 and cps207-2, from two KPC-Kp clinical strains from Italy belonging in sequence type (ST) 258, which is one of the most successful ST of KPC-Kp spreading worldwide. While cpsBO-4 was different from known 78 K-types according to the recently proposed typing schemes based on the wzi or wzc gene sequences, cps207-2 was classified as K41 by one of these methods. Bioinformatic analysis revealed that they were represented in the genomic sequences of KPC-Kp from strains of ST258 from different countries, and cpsBO-4 was also detected in a KPC-Kp strain of ST442 from Brazil. Investigation of a collection of 46 ST258 and ST512 (a single locus variant of ST258) clinical strains representative of the recent Italian epidemic of KPC-Kp by means of a multiplex PCR typing approach revealed that cpsBO-4 was the most prevalent type, being detected both in ST258 and ST512 strains with a countrywide distribution, while cps207-2 was only detected in ST258 strains with a more restricted distribution.

Bacterial identification from blood culture using traditional methods needs about 48 hours, since positivization, to be performed. Rapid bacterial identification can result in clinical and economic benefits. To provide rapid pathogen identification for targeted antibiotic treatment, in this study we tested an our previously described homemade method for bacterial identification using MALDI-TOF directly from positive BACTEC blood culture, on positive BacT/ALERT blood culture. A total of 108 bacteria were identified by MALDI-TOF with a positive identification obtained for 98% of Gram negative and 84,3% of Gram positive bacteria.The average of identification score obtained using the protocol described in this study was 2,047 for Gram positive and 2,204 for Gram negative microorganisms. Data here described show that this method is also useful when BacT/ALERT bottles are used and even if these bottles have activated charcoal as inhibitor of antibiotics.

The spread of enterobacteria producing extended-spectrum ß-lactamases (ESBLs) is sharply increasing in Italy, while the detection of isolates resistant to carbapenems is still sporadic. Isolates of Klebsiella pneumoniae resistant to all cephalosporins, aminoglycosides and fluoroquinolones have been isolated in Trieste since 2008. Because of the altered profile of resistance to carbapenems, these strains were reported as ESBL-negative and possible carbapenemases producer by the expert system, leaving tigecycline as the only therapeutic choice.The purpose of this study is the characterization of the mechanisms involved in resistance to carbapenems in these strains and the evaluation of a reliable and simple test for phenotypic confirmation of ESBL and/or carbapenemase production. 25 isolates of MDR K. pneumoniae were collected between October 2008 and May 2009, mainly from urinary samples of elderly patients hospitalized in medicine wards. Identification and susceptibility testing were performed using the Vitek 2 system.The double-disc (DD) test was used to check the production of ESBLs, while imipenem and imipenem-EDTA synergy test was used to detect the production of metallo-ßlactamase (MBL). Carbapenemase activity was tested by an hydrolysis assay and the production of MBLs was also investigated by PCR. The DD synergy test highlighted the possible production of ESBLs in 18 out of 22 strains, considered as negative by Vitek. All ESBLs producers tested positive for the blaCTX-M-15 allele. Only one isolate was resistant to carbapenems and resulted positive for production of MBL by the phenotypic test.The crude extract showed carbapenemase activity inhibited by EDTA; PCR test gave positive result for a blaVIM-type allele. PCR analysis performed on representative isolates, followed by sequencing, showed that coding sequence of ompk35 was not functional. Results of this study confirmed the emergence of ESBL-positive strains of K. pneumoniae that showed altered sensitivity to carbapenems in absence of carbapenemases. For a correct identification of the resistance mechanisms of these isolates we used phenotypic tests (modified DD test and synergy test for MBL) coupled with molecular techniques.The MDR strains isolated in Trieste are particularly difficult in terms of therapeutic management, especially in case of at-risk subjects.