B-physics from the ratio method with Wilson twisted mass fermions

We present a precise lattice QCD determination of the b-quark mass, of the B and Bs decay constants and first preliminary results for the B-mesons bag parameter. Simulations are performed with Nf = 2 Wilson twisted mass fermions at four values of the lattice spacing and the results are extrapolated to the continuum limit. Our calculation benefits from the use of improved interpolating operators for the B-mesons and employs the so-called ratio method. The latter allows a controlled interpolation at the b-quark mass between the relativistic data around and above the charm quark mass and the exactly known static limit.Comment: 7 pages, 4 figures, 1 table. Proceedings of the 30th International Symposium on Lattice Field Theory - Lattice 2012; June 24-29, 2012; Cairns, Australi

B-physics from lattice QCD...with a twist

We present a precise lattice QCD determination of the b-quark mass, of the B and Bs decay constants and first results for the B-meson bag parameters. For our computation we employ the so-called ratio method and our results benefit from the use of improved interpolating operators for the B-mesons. QCD calculations are performed with Nf = 2 dynamical light-quarks at four values of the lattice spacing and the results are extrapolated to the continuum limit. The preliminary results are mb(mb) = 4.35(12) GeV for the MSbar b-quark mass, fBs = 234(6) MeV and fB = 197(10) MeV for the B-meson decay constants, BBs(mb) = 0.90(5) and BB(mb) = 0.87(5) for the B-meson bag parameters.Comment: 6 pages, 3 figures. Proceedings of the 36th International Conference on High Energy Physics - ICHEP 2012; July 4-11 2012; Melbourne, Australi

Lattice QCD determination of m_b, f_B and f_Bs with twisted mass Wilson fermions

We present a lattice QCD determination of the b quark mass and of the B and B_s decay constants, performed with N_f=2 twisted mass Wilson fermions, by simulating at four values of the lattice spacing. In order to study the b quark on the lattice, two methods are adopted in the present work, respectively based on suitable ratios with exactly known static limit and on the interpolation between relativistic data, evaluated in the charm mass region, and the static point, obtained by simulating the HQET on the lattice. The two methods provide results in good agreement. For the b quark mass in the MSbar scheme and for the decay constants we obtain m_b(m_b)=4.29(14) GeV, f_B=195(12) MeV, f_Bs=232(10) MeV and f_Bs/f_B=1.19(5). As a byproduct of the analysis we also obtain the results for the f_D and f_Ds decay constants: f_D=212(8) MeV, f_Ds=248(6) MeV and f_Ds/f_D=1.17(5).Comment: 23 pages, 10 figures, 2 tables. Added appendix showing the agreement of the data for the ratios with the HQE prediction. Matching JHEP published versio

Light quark masses and pseudoscalar decay constants from Nf=2 Lattice QCD with twisted mass fermions

We present the results of a lattice QCD calculation of the average up-down and strange quark masses and of the light meson pseudoscalar decay constants with Nf=2 dynamical fermions. The simulation is carried out at a single value of the lattice spacing with the twisted mass fermionic action at maximal twist, which guarantees automatic O(a)-improvement of the physical quantities. Quark masses are renormalized by implementing the non-perturbative RI-MOM renormalization procedure. Our results for the light quark masses are m_ud^{msbar}(2 GeV)= 3.85 +- 0.12 +- 0.40 MeV, m_s^{msbar}(2 GeV) = 105 +- 3 +- 9 MeV and m_s/m_ud = 27.3 +- 0.3 +- 1.2. We also obtain fK = 161.7 +- 1.2 +- 3.1 MeV and the ratio fK/fpi=1.227 +- 0.009 +- 0.024. From this ratio, by using the experimental determination of Gamma(K-> mu nu (gamma))/Gamma(pi -> mu nu (gamma)) and the average value of |Vud| from nuclear beta decays, we obtain |Vus|=0.2192(5)(45), in agreement with the determination from Kl3 decays and the unitarity constraint.Comment: 20 pages, 5 figure

B-physics from Nf=2 tmQCD: the Standard Model and beyond

We present a lattice QCD computation of the b-quark mass, the B and B_s decay constants, the B-mixing bag parameters for the full four-fermion operator basis as well as determinations for \xi and f_{Bq}\sqrt{B_i^{(q)}} extrapolated to the continuum limit and to the physical pion mass. We used N_f = 2 twisted mass Wilson fermions at four values of the lattice spacing with pion masses ranging from 280 to 500 MeV. Extrapolation in the heavy quark mass from the charm to the bottom quark region has been carried out on ratios of physical quantities computed at nearby quark masses, exploiting the fact that they have an exactly known infinite mass limit. Our results are m_b(m_b, \overline{\rm{MS}})=4.29(12) GeV, f_{Bs}=228(8) MeV, f_{B}=189(8) MeV and f_{Bs}/f_B=1.206(24). Moreover with our results for the bag-parameters we find \xi=1.225(31), B_1^{(s)}/B_1^{(d)}=1.01(2), f_{Bd}\sqrt{\hat{B}_{1}^{(d)}} = 216(10) MeV and f_{Bs}\sqrt{\hat{B}_{1}^{(s)}} = 262(10) MeV. We also computed the bag parameters for the complete basis of the four-fermion operators which are required in beyond the SM theories. By using these results for the bag parameters we are able to provide a refined Unitarity Triangle analysis in the presence of New Physics, improving the bounds coming from B_{(s)}-\bar B_{(s)} mixing

p53 Regulates Cell Cycle and MicroRNAs to Promote Differentiation of Human Embryonic Stem Cells

Multiple studies show that tumor suppressor p53 is a barrier to dedifferentiation; whether this is strictly due to repression of proliferation remains a subject of debate. Here, we show that p53 plays an active role in promoting differentiation of human embryonic stem cells (hESCs) and opposing self-renewal by regulation of specific target genes and microRNAs. In contrast to mouse embryonic stem cells, p53 in hESCs is maintained at low levels in the nucleus, albeit in a deacetylated, inactive state. In response to retinoic acid, CBP/p300 acetylates p53 at lysine 373, which leads to dissociation from E3-ubiquitin ligases HDM2 and TRIM24. Stabilized p53 binds CDKN1A to establish a G1 phase of cell cycle without activation of cell death pathways. In parallel, p53 activates expression of miR-34a and miR-145, which in turn repress stem cell factors OCT4, KLF4, LIN28A, and SOX2 and prevent backsliding to pluripotency. Induction of p53 levels is a key step: RNA-interference-mediated knockdown of p53 delays differentiation, whereas depletion of negative regulators of p53 or ectopic expression of p53 yields spontaneous differentiation of hESCs, independently of retinoic acid. Ectopic expression of p53R175H, a mutated form of p53 that does not bind DNA or regulate transcription, failed to induce differentiation. These studies underscore the importance of a p53-regulated network in determining the human stem cell state

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Hemophilia Management via Data Collection and Reporting: Initial Findings from the Comprehensive Care Sustainability Collaborative

BACKGROUND: Despite being a rare disorder, hemophilia represents a significant driver of health care resource utilization and requires expert hematologic and multidisciplinary services to achieve optimal outcomes. Since their inception nearly 40 years ago, hemophilia treatment centers (HTCs) have served as centers of excellence in providing the intensive care and ancillary services necessary for this unique patient base; however, the full capabilities of these centers may be underused in the current framework of managed care, largely because of a lack of communication and information shared between payers and HTC stakeholders. PROGRAM DESCRIPTION: In an effort to enact tangible change toward improving the quality of care for bleeding disorders, the National Hemophilia Foundation developed an ongoing initiative among 18 leading clinicians and managed care decision makers called the Comprehensive Care Sustainability Collaborative (CCSC). The primary aim of the CCSC is to develop a framework for quality improvement pilot programs that can be replicated across the United States between payers and HTCs to facilitate cost-effective hemophilia management by integrating the HTC comprehensive care model. OBSERVATIONS: After CCSC committee members shared perspectives on care delivery, quality, and value, actionable data points were reviewed at length in order to develop meaningful metrics to facilitate information sharing between HTC and payer stakeholders. The following pragmatic measures will be reported by HTCs and payers via a series of pilot programs (reporting group is indicated in brackets): (a) patient classification by diagnosis (type, severity, and inhibitor status) [HTC]; (b) total cost of clotting factor [payer]; (c) prescribed factor dose/dispensed dose/patient weight (± range) [payer and HTC]; (d) emergency department visits/hospitalizations [payer and HTC]; (e) home infusion of clotting factor (%) [HTC]; (f) total cost per patient [payer]; and (g) patient contacts (e.g., clinic visits, follow-ups, telemedicine, and e-mail) [HTC]. IMPLICATIONS: Routine information sharing between HTCs and payer stakeholders is paramount to improving the quality and reducing the cost of hemophilia care, and the CCSC initiative provides a unique forum for such dialogue. Over the course of several consensus meetings, the CCSC has rigorously developed a set of quality improvement and cost management metrics. These metrics will be used in a first-of-its-kind series of pilot projects that are anticipated to forge innovative collaboration between payers and HTCs so as to improve outcomes in the management of bleeding disorders. DISCLOSURES: The preparation of this article was funded as part of the Comprehensive Care Sustainability Collaborative (CCSC) initiative, which is jointly sponsored by the National Hemophilia Foundation (NHF) and Impact Education, LLC, and supported via a charitable donation from Shire. Tarantino and Pindolia are members of the CCSC and were part of the NHF CCSC group that developed the metrics included in this article. Both authors received honorariums from the NHF for content development and expert review of the manuscript. Both authors contributed equally to the concept and design of this article and to analysis and manuscript preparation

Matching-Adjusted Indirect Comparison between Personalized Prophylaxis with Simoctocog Alfa Versus Standard Prophylaxis with Emicizumab in Adults with Hemophilia a

Background: Personalized prophylaxis with factor VIII (FVIII) concentrates remains the mainstay therapy for patients with severe hemophilia A. The bispecific monoclonal antibody emicizumab, which mimics FVIII function, is also approved for prophylaxis in hemophilia A patients. Head-to-head comparative studies on the relative efficacy of different therapeutic strategies are not feasible in a rare disease such as hemophilia A. In such situations, the use of indirect comparison methods can help to compare relative efficacies. Matching-adjusted indirect comparison (MAIC) is a well-established statistical method to indirectly compare outcomes from separate clinical studies. It can be used to adjust for differences in patient characteristics between studies, with the goal to reduce bias in the treatment effect estimates which can occur with comparison of efficacy data across clinical trials. Aims: To indirectly compare the efficacy of a pharmacokinetics (PK)-guided personalized prophylaxis regimen with a recombinant, fourth generation, FVIII concentrate, simoctocog alfa (Nuwiq ®), against standard prophylaxis with the bispecific monoclonal antibody emicizumab (Hemlibra ®) in patients with hemophilia A using MAIC methodology. Methods: After matching study populations, accounting for clinically important baseline characteristics,individual patient-level data (IPD) from 65 patients treated with simoctocog alfa from the NuPreviq study were compared against aggregate data for emicizumab administered once weekly (Q1W, N=99), every 2 weeks (Q2W, N=35) or every 4 weeks (Q4W, N=41) from the HAVEN 3 and HAVEN 4 studies. All patients enrolled in all studies were male. Baseline patient variables for matching were chosen based on availability, clinical relevance and distribution overlap. Baseline age and body weight were used to re-weight the simoctocog alfa IPD to match the aggregate data reported for the emicizumab studies. Patients were removed from the NuPreviq study population if they did not meet the eligibility criteria for the comparator studies (but none were excluded from this analysis based on this). Unanchored indirect treatment comparisons were performed for various clinical outcomes using the re-weighted data for simoctocog alfa and the published comparator study data. The endpoints analyzed were total annualized bleeding rates (ABRs) and percentage of patients with zero bleeds. All endpoints considered treated and untreated bleeds. Results: No patients were excluded from the NuPreviq study population due to imposing the body weight or age criteria of the HAVEN 3 and 4 studies. After matching populations, the effective sample size for simoctocog alfa was 33.1, 39.8 and 29.1 participants for the Q1W, Q2W and Q4W comparisons, respectively. The percentage of patients with zero bleeds was significantly higher with simoctocog alfa across all 3 comparisons: simoctocog alfa (74.3%) vs emicizumab Q1W (46.5%); simoctocog alfa (70.3%) vs emicizumab Q2W (40.0%), and simoctocog alfa (81.9%) vs emicizumab Q4W (29.3%; Figure 1, Table 1). The total ABRs were significantly lower with simoctocog alfa versus emicizumab Q1W (1.5 vs 2.9) and emicizumab Q4W (1.4 vs 4.5; Table 1). When comparing simoctocog alfa versus emicizumab Q2W, the difference was not statistically significant (1.3 vs 2.6; Table 1). Conclusion: Indirect comparisons demonstrated that PK-guided, personalized prophylaxis with simoctocog alfa can lead to statistically significantly higher zero bleed rates and decreased ABRs compared with standard emicizumab prophylaxis. This MAIC analysis provides important comparative efficacy and utilization data, which can help guide patients and physicians in making decisions regarding product choice for prophylaxis regimens