CKM angle γ measurements at LHCb

International audienceThe CKM angle γ remains the least known parameter of the CKM mixing matrix. The precise measurement of this angle, as a Standard Model benchmark, is a key goal of the LHCb experiment. We present four recent CP violation studies related to the measurement of γ, including amplitude analysis of B± → DK± decays, the ADS/GLW analysis of B± → DK*0 decays and the time-dependent analysis of B± → DK±sK± decays

Generation of Distal Airway Epithelium from Multipotent Human Foregut Stem Cells.

Collectively, lung diseases are one of the largest causes of premature death worldwide and represent a major focus in the field of regenerative medicine. Despite significant progress, only few stem cell platforms are currently available for cell-based therapy, disease modeling, and drug screening in the context of pulmonary disorders. Human foregut stem cells (hFSCs) represent an advantageous progenitor cell type that can be used to amplify large quantities of cells for regenerative medicine applications and can be derived from any human pluripotent stem cell line. Here, we further demonstrate the application of hFSCs by generating a near homogeneous population of early pulmonary endoderm cells coexpressing NKX2.1 and FOXP2. These progenitors are then able to form cells that are representative of distal airway epithelium that express NKX2.1, GATA6, and cystic fibrosis transmembrane conductance regulator (CFTR) and secrete SFTPC. This culture system can be applied to hFSCs carrying the CFTR mutation Δf508, enabling the development of an in vitro model for cystic fibrosis. This platform is compatible with drug screening and functional validations of small molecules, which can reverse the phenotype associated with CFTR mutation. This is the first demonstration that multipotent endoderm stem cells can differentiate not only into both liver and pancreatic cells but also into lung endoderm. Furthermore, our study establishes a new approach for the generation of functional lung cells that can be used for disease modeling as well as for drug screening and the study of lung development.This work was funded by the ERC starting grant Relieve IMDs (L.V.), the Cambridge Hospitals National Institute for Health Research Biomedical Research Center (L.V., N.R.F.H.), and the Evelyn trust (N.R.F.H.). N.A.H. is a Wellcome Trust senior clinical fellow (WT088566, WT097820). F.S. has been funded by an ACT Clinical Research Training Fellowship and a joint Sparks-MRC Clinical Research Training Fellowship. C.-P.S. is funded by the Children's Liver Diseases Foundation.This is the final version of the article. It first appeared from Mary Ann Liebert Publishers via http://dx.doi.org/10.1089/scd.2014.051

Is Early Appropriate Care of axial and femoral fractures appropriate in multiply-injured elderly trauma patients?

BACKGROUND: Previous work established resuscitation parameters that minimize complications with early fracture management. This Early Appropriate Care (EAC) protocol was applied to patients with advanced age to determine if they require unique parameters to mitigate complications. METHODS: Between October 2010 and March 2013, 376 consecutive skeletally mature patients with unstable fractures of the pelvis, acetabulum, thoracolumbar spine, and/or proximal or diaphyseal femur fractures were treated at a level I trauma center and were prospectively studied. Patients aged ≤30 years (n = 114), 30 to 60 years (n = 184), and ≥60 years (n = 37) with Injury Severity Scores (ISS) ≥16 and unstable fractures of the pelvis, acetabulum, spine, and/or diaphyseal femur were treated within 36 h, provided they showed evidence of adequate resuscitation. ISS, Glasgow Coma Scale (GCS), and American Society of Anesthesiologists (ASA) classification were determined. Lactate, pH, and base excess (BE) were measured at 8-h intervals. Complications included pneumonia, pulmonary embolism (PE), acute renal failure, acute respiratory distress syndrome (ARDS), multiple organ failure (MOF), deep vein thrombosis, infection, sepsis, and death. RESULTS: Patients ≤30 years old (y/o) were more likely to sustain gunshot wounds (p = 0.039), while those ≥60 y/o were more likely to fall from a height (p = 0.002). Complications occurred at similar rates for patients ≤30 y/o, 30 to 60 y/o, and ≥60 y/o. There were no differences in lactate, pH, or BE at the time of surgery. For patients ≤30 y/o, there were increased overall complications if pH was <7.30 (p = 0.042) or BE <−6.0 (p = 0.049); patients ≥60 y/o demonstrated more sepsis if BE was <−6.0 (p = 0.046). CONCLUSIONS: EAC aims to definitively manage axial and femoral shaft fractures once patients have been adequately resuscitated to minimize complications. EAC is associated with comparable complication rates in young and elderly patients. Further study is warranted with a larger sample to further validate EAC in elderly patients. Level of evidence: level II prospective, comparative study

Inhibition of activin/nodal signalling is necessary for pancreatic differentiation of human pluripotent stem cells

Peer reviewedPublisher PD

TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors

PMCID: PMC4434585.-- et al.The genomic regulatory programmes that underlie human organogenesis are poorly understood. Pancreas development, in particular, has pivotal implications for pancreatic regeneration, cancer and diabetes. We have now characterized the regulatory landscape of embryonic multipotent progenitor cells that give rise to all pancreatic epithelial lineages. Using human embryonic pancreas and embryonic-stem-cell-derived progenitors we identify stage-specific transcripts and associated enhancers, many of which are co-occupied by transcription factors that are essential for pancreas development. We further show that TEAD1, a Hippo signalling effector, is an integral component of the transcription factor combinatorial code of pancreatic progenitor enhancers. TEAD and its coactivator YAP activate key pancreatic signalling mediators and transcription factors, and regulate the expansion of pancreatic progenitors. This work therefore uncovers a central role for TEAD and YAP as signal-responsive regulators of multipotent pancreatic progenitors, and provides a resource for the study of embryonic development of the human pancreas.The research was supported by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre. Work was funded by grants from the Ministerio de Economía y Competitividad (CB07/08/0021, SAF2011-27086, PLE2009-0162 to J.F., BFU2013-41322-P to J.L.G-S.), the Andalusian Government (BIO-396 to J.L.G-S.), the Wellcome Trust (WT088566 and WT097820 to N.A.H., WT101033 to J.F.), the Manchester Biomedical Research Centre, ERC advanced starting grant IMDs (C.H-H.C. and L.V.) and the Cambridge Hospitals National Institute for Health Research Biomedical Research Centre (L.V.). R.E.J. is a Medical Research Council clinical training fellow. The authors are grateful to C. Wright (Vanderbilt University) for zebrafish Pdx1 antiserum, J. Postlethwait (Purdue University) for a Sox9b clone, H. Sasaki (Kumamoto University) for a TEAD–EnR clone, C. Vinod and L. Abi for research nurse assistance, and clinical colleagues at Central Manchester University Hospitals NHS Foundation Trust. The authors thank J. Garcia-Hurtado for technical assistance (IDIBAPS).Peer Reviewe

Low Bone Mineral Density, Renal Dysfunction, and Fracture Risk in HIV Infection: A Cross-Sectional Study

BackgroundReduced bone mineral density (BMD) is common in adults infected with human immunodeficiency virus (HIV). The role of proximal renal tubular dysfunction (PRTD) and alterations in bone metabolism in HIV-related low BMD are incompletely understood MethodsWe quantified BMD (dual-energy x-ray absorptiometry), blood and urinary markers of bone metabolism and renal function, and risk factors for low BMD (hip or spine T score, −1 or less) in an ambulatory care setting. We determined factors associated with low BMD and calculated 10-year fracture risks using the World Health Organization FRAX equation ResultsWe studied 153 adults (98% men; median age, 48 years; median body mass index, 24.5; 67 [44%] were receiving tenofovir, 81 [53%] were receiving a boosted protease inhibitor [PI]). Sixty-five participants (42%) had low BMD, and 11 (7%) had PRTD. PI therapy was associated with low BMD in multivariable analysis (odds ratio, 2.69; 95% confidence interval, 1.09-6.63). Tenofovir use was associated with increased osteoblast and osteoclast activity (P⩽.002). The mean estimated 10-year risks were 1.2% for hip fracture and 5.4% for any major osteoporotic fracture ConclusionsIn this mostly male population, low BMD was significantly associated with PI therapy. Tenofovir recipients showed evidence of increased bone turnover. Measurement of BMD and estimation of fracture risk may be warranted in treated HIV-infected adult

On the motivations for Merleau-Ponty’s ontological research

This paper attempts to clarify Merleau-Ponty’s later work by tracing a hitherto overlooked set of concerns that were of key consequence for the formulation of his ontological research. I argue that his ontology can be understood as a response to a set of problems originating in reflections on the intersubjective use of language in dialogue, undertaken in the early 1950s. His study of dialogue disclosed a structure of meaning-formation and pointed towards a theory of truth (both recurring ontological topics) that post-Phenomenology premises could not account for. A study of dialogue shows that speakers’ positions are interchangeable, that speaking subjects are active and passive in varying degrees, and that the intentional roles of subjects and objects are liable to shift or ‘transgress’ themselves. These observations anticipate the concepts of ‘reversibility’ and ‘narcissism’, his later view of activity and passivity, and his later view of intentionality, and sharpened the need to adopt an intersubjective focus in ontological research

Differential branching fraction and angular analysis of Λb0→Λμ+μ−\Lambda^{0}_{b} \rightarrow \Lambda \mu^+\mu^- decays

The differential branching fraction of the rare decay $\Lambda^{0}_{b} \rightarrow \Lambda \mu^+\mu^-$ is measured as a function of $q^{2}$, the square of the dimuon invariant mass. The analysis is performed using proton-proton collision data, corresponding to an integrated luminosity of 3.0 \mbox{ fb}^{-1}, collected by the LHCb experiment. Evidence of signal is observed in the $q^2$ region below the square of the $J/\psi$ mass. Integrating over 15 < q^{2} < 20 \mbox{ GeV}^2/c^4 the branching fraction is measured as d\mathcal{B}(\Lambda^{0}_{b} \rightarrow \Lambda \mu^+\mu^-)/dq^2 = (1.18 ^{+ 0.09} _{-0.08} \pm 0.03 \pm 0.27) \times 10^{-7} ( \mbox{GeV}^{2}/c^{4})^{-1}, where the uncertainties are statistical, systematic and due to the normalisation mode, $\Lambda^{0}_{b} \rightarrow J/\psi \Lambda$, respectively. In the $q^2$ intervals where the signal is observed, angular distributions are studied and the forward-backward asymmetries in the dimuon ($A^{l}_{\rm FB}$) and hadron ($A^{h}_{\rm FB}$) systems are measured for the first time. In the range 15 < q^2 < 20 \mbox{ GeV}^2/c^4 they are found to be A^{l}_{\rm FB} = -0.05 \pm 0.09 \mbox{ (stat)} \pm 0.03 \mbox{ (syst)} and A^{h}_{\rm FB} = -0.29 \pm 0.07 \mbox{ (stat)} \pm 0.03 \mbox{ (syst)}.Comment: 27 pages, 10 figures, Erratum adde

Observation of the decay Bc→J/ψK+K−π+B_c \rightarrow J/\psi K^+ K^- \pi^+

The decay $B_c\rightarrow J/\psi K^+ K^- \pi^+$ is observed for the first time, using proton-proton collisions collected with the LHCb detector corresponding to an integrated luminosity of 3fb$^{-1}$. A signal yield of $78\pm14$ decays is reported with a significance of 6.2 standard deviations. The ratio of the branching fraction of \B_c \rightarrow J/\psi K^+ K^- \pi^+ decays to that of $B_c \rightarrow J/\psi \pi^+$ decays is measured to be $0.53\pm 0.10\pm0.05$, where the first uncertainty is statistical and the second is systematic.Comment: 18 pages, 2 figure

Trastuzumab-associated cardiac events in the Persephone trial

Background:We report cardiac events in the Persephone trial which compares 6–12 months of adjuvant trastuzumab in women with confirmed HER2-positive, early-stage breast cancer. Methods:Clinical cardiac events were defined as any of the following: symptoms and/or signs of congestive heart failure (CHF) and new or altered CHF medication. In addition, left ventricular ejection fraction (LVEF) was measured at baseline and then 3 monthly for 12 months. Results:A total of 2500 patients, aged 22–82, were included: 1251 randomised to 12 months and 1249 to 6 months of trastuzumab treatment. A total of 93% (2335/2500) received anthracyclines, 49% of these (1136/2335) with taxanes. Cardiotoxicity delayed treatment in 6% of 12-month and 4% of 6-month patients (P=0.01), and stopped treatment early in 8% (96/1214) of 12-month and 4% (45/1216) of 6-month patients (P3 cycles of anthracycline was associated with higher risk of cardiac events only for 12-month patients (OR 1.41 (1.04–1.90)), and not for 6-month patients (OR 1.28 (0.91–1.79)). Conclusions:We demonstrate significantly fewer cardiac events from 6 months of adjuvant trastuzumab compared with that from 12 months. This cardiac signal adds importance to the question of the optimum duration of adjuvant trastuzumab treatment. If 6 months is proven to have non-inferior outcomes to 12 months treatment, these data would support 6 months as the standard of care