Performance of hybrid photon detectors and studies of two-body hadronic B decays at LHCb

The LHCb experiment at the CERN LHC accelerator will begin physics data taking in late 2009. LHCb aims to discover New Physics processes via precision measurements using heavy flavoured hadrons, such as B and D hadrons. This thesis describes studies relevant to measurements of B decays to hadronic final states at LHCb. The Ring Imaging Cherenkov (RICH) counters of LHCb are crucial to the performance of such measurements. They use arrays of Hybrid Photon Detectors (HPDs) as their photodetection system. Detailed results are presented from the characterisation programme of the entire sample of 557 HPDs that were produced. Their overall performance is found to be outstanding, with only 2.2% of HPDs judged to be unusable for the RICHes. The LHCb requirements and the contractual specifications are met and often exceeded in key areas. The measurement of the single photoelectron detection efficiency, eta, of the HPD anode is described in detail. The efficiency was measured as eta = (87.9 +/- 1.4)%. This value exceeds the LHCb-RICH requirement, and is in agreement with previous measurements. A method to measure the detector proper time resolution for two-body hadronic B decays from data, making use of the per-event proper time error, is described. A proper time resolution model is proposed and is shown to accurately match the simulated resolution for these decays. The model parameters can be measured on data by fitting the flavour-tagged proper time distribution of the Bs->K-Pi+ decay. Constraining the proper time resolution model via this method can potentially reduce systematic errors in time-dependent studies. A study is presented which examines the prospects of LHCb to discover new baryonic B decay modes, with particular focus on the experimentally most promising mode, Bd->ppbar. It is found that a 5 sigma discovery of Bd->ppbar is possible with only 0.25 fb^-1 of nominal LHCb data, if its true branching fraction is close to the current experimental upper limit. Finally, the prospects of LHCb to measure the direct and mixing-induced CP asymmetries for the decay Bd->Pi+Pi-, via a time-dependent study, are assessed. A fit is made to the invariant mass and proper time distributions of simulated data. The total sensitivities with early data (0.3 fb^-1) are found to be 0.135(stat) + 0.012(syst) and 0.093(stat) + 0.018(syst) for the direct and mixing-induced asymmetries respectively. These sensitivities are competitive with current experimental measurements, and indicate that LHCb will come to dominate the world average values for these CP asymmetries as more data is collected

Dysregulated Cytokine Expression by CD4+ T cells from Post-Septic Mice Modulates both Th1 and Th2-Mediated Granulomatous Lung Inflammation

Previous epidemiological studies in humans and experimental studies in animals indicate that survivors of severe sepsis exhibit deficiencies in the activation and effector function of immune cells. In particular, CD4+ T lymphocytes can exhibit reduced proliferative capacity and improper cytokine responses following sepsis. To further investigate the cell-intrinsic defects of CD4+ T cells following sepsis, splenic CD4+ T cells from sham surgery and post-septic mice were transferred into lymphopenic mice. These recipient mice were then subjected to both TH1-(purified protein derivative) and TH2-(Schistosoma mansoni egg antigen) driven models of granulomatous lung inflammation. Post-septic CD4+ T cells mediated smaller TH1 and larger TH2 lung granulomas as compared to mice receiving CD4+ T cells from sham surgery donors. However, cytokine production by lymph node cells in antigen restimulation assays indicated increased pan-specific cytokine expression by post-septic CD4+ T cell recipient mice in both TH1 and TH2 granuloma models. These include increased production of TH2 cytokines in TH1 inflammation, and increased production of TH1 cytokines in TH2 inflammation. These results suggest that cell-intrinsic defects in CD4+ T cell effector function can have deleterious effects on inflammatory processes post-sepsis, due to a defect in the proper regulation of TH-specific cytokine expression

Measurement of the Xi(-)(b) and Omega(-)(b) baryon lifetimes

Using a data sample of pp collisions corresponding to an integrated luminosity of 3 fb(-1), the Xi(-)(b) and Omega(-)(b) baryons are reconstructed in the Xi(-)(b) -&gt; J/psi Xi(-) and Omega(-)(b) -&gt; J/psi Omega(-) decay modes and their lifetimes measured to betau(Xi(-)(b)) = 1.55(-0.09)(+0.10) (stat) +/- 0.03 (syst) ps,tau(Omega(-)(b)) = 1.54(-0.21)(+0.26) (stat) +/- 0.05 (syst) ps.These are the most precise determinations to date. Both measurements are in good agreement with previous experimental results and with theoretical predictions. (C) 2014 The Authors. Published by Elsevier B.V.</p

First observations of the rare decays B (+) -&gt; K (+)pi (+)pi (-)mu(+)mu (-) and B (+)-&gt; phi K (+)mu(+)mu (-)

First observations of the rare decays B (+) -> K (+)pi (+) pi (-) mu (+) mu (-) and B (+)-> phi K+ mu(+)mu(-) are presented using data corresponding to an integrated luminosity of 3.0 fb(-1), collected by the LHCb experiment at centre-of-mass energies of 7 and 8 TeV. The branching fractions of the decays are B(B (+) -> K (+)pi (+) pi (-) mu (+) mu (-) ) = (4.36 (-0.27) (+0.29) (stat) +/- 0.21 (syst) +/- (norm)) x 10(-7), B(B (+)-> phi K+ mu(+)mu(-)) = (0.82 (+0.19)(-0.17) (stat) (+0.10)(-0.04) (syst) +/- 0.27 (norm)) x 10(-7) where the uncertainties are statistical, systematic, and due to the uncertainty on the branching fractions of the normalisation modes. A measurement of the differential branching fraction in bins of the invariant mass squared of the dimuon system is also presented for the decay B (+) -> K (+)pi (+) pi (-) mu (+) mu (-

HUS and atypical HUS

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by intravascular hemolysis, thrombocytopenia, and acute kidney failure. HUS is usually categorized as typical, caused by Shiga toxin-producing Escherichia coli (STEC) infection, as atypical HUS (aHUS), usually caused by uncontrolled complement activation, or as secondary HUS with a coexisting disease. In recent years, a general understanding of the pathogenetic mechanisms driving HUS has increased. Typical HUS (ie, STEC-HUS) follows a gastrointestinal infection with STEC, whereas aHUS is associated primarily with mutations or autoantibodies leading to dysregulated complement activation. Among the 30% to 50% of patients with HUS who have no detectable complement defect, some have either impaired diacylglycerol kinase epsilon (DGK epsilon) activity, cobalamin C deficiency, or plasminogen deficiency. Some have secondary HUS with a coexisting disease or trigger such as autoimmunity, transplantation, cancer, infection, certain cytotoxic drugs, or pregnancy. The common pathogenetic features in STEC-HUS, aHUS, and secondary HUS are simultaneous damage to endothelial cells, intravascular hemolysis, and activation of platelets leading to a procoagulative state, formation of microthrombi, and tissue damage. In this review, the differences and similarities in the pathogenesis of STEC-HUS, aHUS, and secondaryHUSare discussed. Commonfor the pathogenesis seems to be the vicious cycle of complement activation, endothelial cell damage, platelet activation, and thrombosis. This process can be stopped by therapeutic complement inhibition in most patients with aHUS, but usually not those with a DGK epsilon mutation, and some patients with STEC-HUS or secondary HUS. Therefore, understanding the pathogenesis of the different forms of HUS may prove helpful in clinical practice.Peer reviewe

Defining the Critical Hurdles in Cancer Immunotherapy

ABSTRACT: Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators, others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet be overcome to improve outcomes of patients with cancer

Defining the critical hurdles in cancer immunotherapy

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer

Procalcitonin Is Not a Reliable Biomarker of Bacterial Coinfection in People With Coronavirus Disease 2019 Undergoing Microbiological Investigation at the Time of Hospital Admission

Abstract Admission procalcitonin measurements and microbiology results were available for 1040 hospitalized adults with coronavirus disease 2019 (from 48 902 included in the International Severe Acute Respiratory and Emerging Infections Consortium World Health Organization Clinical Characterisation Protocol UK study). Although procalcitonin was higher in bacterial coinfection, this was neither clinically significant (median [IQR], 0.33 [0.11–1.70] ng/mL vs 0.24 [0.10–0.90] ng/mL) nor diagnostically useful (area under the receiver operating characteristic curve, 0.56 [95% confidence interval, .51–.60]).</jats:p