Ten years ago, a consensus report on the optimization of tacrolimus was published in this journal. In 2017, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicity (IATDMCT) decided to issue an updated consensus report considering the most relevant advances in tacrolimus pharmacokinetics (PK), pharmacogenetics (PG), pharmacodynamics, and immunologic biomarkers, with the aim to provide analytical and drug-exposure recommendations to assist TDM professionals and clinicians to individualize tacrolimus TDM and treatment. The consensus is based on in-depth literature searches regarding each topic that is addressed in this document. Thirty-seven international experts in the field of TDM of tacrolimus as well as its PG and biomarkers contributed to the drafting of sections most relevant for their expertise. Whenever applicable, the quality of evidence and the strength of recommendations were graded according to a published grading guide. After iterated editing, the final version of the complete document was approved by all authors. For each category of solid organ and stem cell transplantation, the current state of PK monitoring is discussed and the specific targets of tacrolimus trough concentrations (predose sample C0) are presented for subgroups of patients along with the grading of these recommendations. In addition, tacrolimus area under the concentration–time curve determination is proposed as the best TDM option early after transplantation, at the time of immunosuppression minimization, for special populations, and specific clinical situations. For indications other than transplantation, the potentially effective tacrolimus concentrations in systemic treatment are discussed without formal grading. The importance of consistency, calibration, proficiency testing, and the requirement for standardization and need for traceability and reference materials is highlighted. The status for alternative approaches for tacrolimus TDM is presented including dried blood spots, volumetric absorptive microsampling, and the development of intracellular measurements of tacrolimus. The association between CYP3A5 genotype and tacrolimus dose requirement is consistent (Grading A I). So far, pharmacodynamic and immunologic biomarkers have not entered routine monitoring, but determination of residual nuclear factor of activated T cells–regulated gene expression supports the identification of renal transplant recipients at risk of rejection, infections, and malignancy (B II). In addition, monitoring intracellular T-cell IFN-g production can help to identify kidney and liver transplant recipients at high risk of acute rejection (B II) and select good candidates for immunosuppression minimization (B II). Although cell-free DNA seems a promising biomarker of acute donor injury and to assess the minimally effective C0 of tacrolimus, multicenter prospective interventional studies are required to better evaluate its clinical utility in solid organ transplantation. Population PK models including CYP3A5 and CYP3A4 genotypes will be considered to guide initial tacrolimus dosing. Future studies should investigate the clinical benefit of time-to-event models to better evaluate biomarkers as predictive of personal response, the risk of rejection, and graft outcome. The Expert Committee concludes that considerable advances in the different fields of tacrolimus monitoring have been achieved during this last decade. Continued efforts should focus on the opportunities to implement in clinical routine the combination of new standardized PK approaches with PG, and valid biomarkers to further personalize tacrolimus therapy and to improve long-term outcomes for treated patients.
A narrow pentaquark state, P c ð4312Þ þ , decaying to J=ψp, is discovered with a statistical significance of 7.3σ in a data sample of Λ 0 b → J=ψpK − decays, which is an order of magnitude larger than that previously analyzed by the LHCb Collaboration. The P c ð4450Þ þ pentaquark structure formerly reported by LHCb is confirmed and observed to consist of two narrow overlapping peaks, P c ð4440Þ þ and P c ð4457Þ þ , where the statistical significance of this two-peak interpretation is 5.4σ. The proximity of the Σ þ cD 0 and Σ þ cD Ã0 thresholds to the observed narrow peaks suggests that they play an important role in the dynamics of these states.
A test of lepton universality, performed by measuring the ratio of the branching fractions of the B 0 → K * 0 µ + µ − and B 0 → K * 0 e + e − decays, R K * 0 , is presented. The K * 0 meson is reconstructed in the final state K + π − , which is required to have an invariant mass within 100 MeV/c 2 of the known K * (892) 0 mass. The analysis is performed using proton-proton collision data, corresponding to an integrated luminosity of about 3 fb −1 , collected by the LHCb experiment at centre-of-mass energies of 7 and 8 TeV. The ratio is measured in two regions of the dilepton invariant mass squared, q 2 , to be− 0.07 (stat) ± 0.03 (syst) for 0.045 < q 2 < 1.1 GeV 2 /c 4 , 0.69 + 0.11 − 0.07 (stat) ± 0.05 (syst) for 1.1 < q 2 < 6.0 GeV 2 /c 4 .The corresponding 95.4% confidence level intervals are [0.52, 0.89] and [0.53, 0.94]. The results, which represent the most precise measurements of R K * 0 to date, are compatible with the Standard Model expectations at the level of 2.1-2.3 and 2.4-2.5 standard deviations in the two q 2 regions, respectively.
A measurement of the ratio of branching fractions of the decays B þ → K þ μ þ μ − and B þ → K þ e þ e − is presented. The proton-proton collision data used correspond to an integrated luminosity of 5.0 fb −1 recorded with the LHCb experiment at center-of-mass energies of 7, 8, and 13 TeV. For the dilepton mass-squared range 1.1 < q 2 < 6.0 GeV 2 =c 4 the ratio of branching fractions is measured to be R K ¼ 0.846 þ0.060 −0.054 þ0.016 −0.014 , where the first uncertainty is statistical and the second systematic. This is the most precise measurement of R K to date and is compatible with the standard model at the level of 2.5 standard deviations.
Test of lepton flavor universality by the measurement of the B 0 → D Ã − τ + ν τ branching fraction using three-prong τ decays R. Aaij et al.
Background Beta-lactam antibiotics (βLA) are the most commonly used antibiotics in the intensive care unit (ICU). ICU patients present many pathophysiological features that cause pharmacokinetic (PK) and pharmacodynamic (PD) specificities, leading to the risk of underdosage. The French Society of Pharmacology and Therapeutics (SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (SFAR) have joined forces to provide guidelines on the optimization of beta-lactam treatment in ICU patients. Methods A consensus committee of 18 experts from the two societies had the mission of producing these guidelines. The entire process was conducted independently of any industry funding. A list of questions formulated according to the PICO model (Population, Intervention, Comparison, and Outcomes) was drawn-up by the experts. Then, two bibliographic experts analysed the literature published since January 2000 using predefined keywords according to PRISMA recommendations. The quality of the data identified from the literature was assessed using the GRADE® methodology. Due to the lack of powerful studies having used mortality as main judgement criteria, it was decided, before drafting the recommendations, to formulate only “optional” recommendations. Results After two rounds of rating and one amendment, a strong agreement was reached by the SFPT-SFAR guideline panel for 21 optional recommendations and a recapitulative algorithm for care covering four areas: (i) pharmacokinetic variability, (ii) PK-PD relationship, (iii) administration modalities, and (iv) therapeutic drug monitoring (TDM). The most important recommendations regarding βLA administration in ICU patients concerned (i) the consideration of the many sources of PK variability in this population; (ii) the definition of free plasma concentration between four and eight times the Minimal Inhibitory Concentration (MIC) of the causative bacteria for 100% of the dosing interval as PK-PD target to maximize bacteriological and clinical responses; (iii) the use of continuous or prolonged administration of βLA in the most severe patients, in case of high MIC bacteria and in case of lower respiratory tract infection to improve clinical cure; and (iv) the use of TDM to improve PK-PD target achievement. Conclusions The experts strongly suggest the use of personalized dosing, continuous or prolonged infusion and therapeutic drug monitoring when administering βLA in critically ill patients. Electronic supplementary material The online version of this article (10.1186/s13054-019-2378-9) contains supplementary material, which is available to authorized users.
The role of p53, as a prognostic factor for survival in lung cancer, is controversial and the purpose of the present systematic review of the literature is to determine this effect.Published studies were identified with the objective to aggregate the available survival results after a methodological assessment using a scale specifically designed by the European Lung Cancer Working Party (ELCWP). To be eligible, a study had to deal with p53 assessment in lung cancer (primary site) only, and to provide a survival comparison according to the p53 status.Among the 74 eligible papers, 30 identified p53 abnormalities as a univariate statistically significant poor prognostic factor and 56 provided sufficient data to allow survival results aggregation. There was no significant difference between the trials that either showed or did not show a prognostic effect of p53 according to the methodological score or to the laboratory technique used. The studies were categorized by histology, disease stage, treatment and laboratory technique. Combined hazard ratios suggested that an abnormal p53 status had an unfavourable impact on survival: in any stage nonsmall cell lung cancer (NSCLC) the mean (95% confidence interval) was 1.44 (1.20-1.72) (number of studies included in the subgroup was 11), 1.50 (1.32-1.70) in stages I-II NSCLC (n=19), 1.68 (1.23-2.29) in stages I-IIIB NSCLC (n=5), 1.68 (1.30-2.18) in stages III-IV NSCLC (n=9), 1.48 (1.29-1.70) in surgically resected NSCLC (n=20), 1.37 (1.02-1.85) in squamous cell carcinoma (n=9), 2.24 (1.70-2.95) in adenocarcinoma (n=9), 1.57 (1.28-1.91) for a positive immunohistochemistry with antibody 1801 (n=8), 1.25 (1.09-1.43) for a positive immunohistochemistry with antibody DO-7 (n=16), and 1.65 (1.35-2.00) for an abnormal molecular biology test (n=13). Data were insufficient to determine the prognostic value of p53 in small cell lung cancer.In each subgroup of nonsmall cell lung cancer, p53 abnormal status was shown to be associated with a poorer survival prognosis. Lung cancer is the most common cause of cancer death in industrialized countries and its incidence is steadily increasing in females and in many European countries. Despite improvements in diagnosis and therapy, the overall 5-yr survival is still 15%.Some independent prognostic factors have been identified for predicting survival and helping in the management of patients with lung cancer [1]. They include: for small cell lung cancer (SCLC), extent of disease and performance status (PS) [2]; for resectable nonsmall cell lung cancer (NSCLC), PS, tumour, node, metastasis (TNM) stage, and age [3]; for advanced NSCLC, PS, TNM stage, age, sex and weight loss [4,5]. Among biological factors, white blood cell count, serum lactate dehydrogenase level, angiogenesis and factors reflecting proliferative state have been shown to significantly predict outcome [6,7].Recent progresses in molecular biology have allowed for the extension of the research on prognostic factors to the analysis of proteins and genes involved in cancer...
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