Utilization of data below the analytical limit of quantitation in pharmacokinetic analysis and modeling: promoting interdisciplinary debate

Traditionally, bioanalytical laboratories do not report actual concentrations for samples with results below the LOQ (BLQ) in pharmacokinetic studies. BLQ values are outside the method calibration range established during validation and no data are available to support the reliability of these values. However, ignoring BLQ data can contribute to bias and imprecision in model-based pharmacokinetic analyses. From this perspective, routine use of BLQ data would be advantageous. We would like to initiate an interdisciplinary debate on this important topic by summarizing the current concepts and use of BLQ data by regulators, pharmacometricians and bioanalysts. Through introducing the limit of detection and evaluating its variability, BLQ data could be released and utilized appropriately for pharmacokinetic research

Test beam performance of a CBC3-based mini-module for the Phase-2 CMS Outer Tracker before and after neutron irradiation

The Large Hadron Collider (LHC) at CERN will undergo major upgrades to increase the instantaneous luminosity up to 5–7.5×10$^{34}$ cm$^{-2}$s$^{-1}$. This High Luminosity upgrade of the LHC (HL-LHC) will deliver a total of 3000–4000 fb-1 of proton-proton collisions at a center-of-mass energy of 13–14 TeV. To cope with these challenging environmental conditions, the strip tracker of the CMS experiment will be upgraded using modules with two closely-spaced silicon sensors to provide information to include tracking in the Level-1 trigger selection. This paper describes the performance, in a test beam experiment, of the first prototype module based on the final version of the CMS Binary Chip front-end ASIC before and after the module was irradiated with neutrons. Results demonstrate that the prototype module satisfies the requirements, providing efficient tracking information, after being irradiated with a total fluence comparable to the one expected through the lifetime of the experiment

Evaluation of HPK +- planar pixel sensors for the CMS Phase-2 upgrade

Data availability: Data will be made available on request.The article archived on this institutional repository is a preprint made available on arXiv, arXiv:2212.04793v1 [physics.ins-det] (license: CC BY-NC-ND 4.0 - https://creativecommons.org/licenses/by-nc-nd/4.0/). It has not been certified by peer review. You are advised to consult the final version published by Elsevier at: https://doi.org/10.1016/j.nima.2023.168326 (the pubished version is copyright © 2023 Elsevier B.V. All rights reserved).To cope with the challenging environment of the planned high luminosity upgrade of the Large Hadron Collider (HL-LHC), scheduled to start operation in 2029, CMS will replace its entire tracking system. The requirements for the tracker are largely determined by the long operation time of 10 years with an instantaneous peak luminosity of up to 7.5 × 10^34 cm^−2^s−1 in the ultimate performance scenario. Depending on the radial distance from the interaction point, the silicon sensors will receive a particle fluence corresponding to a non-ionizing energy loss of up to Φeq = 3.5 × 10^16 cm^−2. This paper focuses on planar pixel sensor design and qualification up to a fluence of Φeq = 1.4 × 10^16 cm^−2. For the development of appropriate planar pixel sensors an R&D program was initiated, which includes n+-p sensors on 150 mm (6'') wafers with an active thickness of 150 μm with pixel sizes of 100 × 25 μm^2 and 50 × 50 μm^2 manufactured by Hamamatsu Photonics K.K. (HPK). Single chip modules with ROC4Sens and RD53A readout chips were made. Irradiation with protons and neutrons, as well was an extensive test beam campaign at DESY were carried out. This paper presents the investigation of various assemblies mainly with ROC4Sens readout chips. It demonstrates that multiple designs fulfill the requirements in terms of breakdown voltage, leakage current and efficiency. The single point resolution for 50 × 50 μm^2 pixels is measured as 4.0 μm for non-irradiated samples, and 6.3 μm after irradiation to Φeq = 7.2 × 10^15 cm^−2.This work was supported by the German Federal Ministry of Education and Research (BMBF) in the framework of the “FIS-Projekt - Fortführung des CMS-Experiments zum Einsatz am HL-LHC: Verbesserung des Spurdetektors für das Phase-2 Upgrade des CMS-Experiments” and supported by the H2020 project AIDA-2020, GA no. 654168. The measurements leading to these results have been performed at the Test Beam Facility at DESY Hamburg (Germany), a member of the Helmholtz Association (HGF). The tracker groups gratefully acknowledge financial support from the following funding agencies: BMWFW and FWF (Austria); FNRS, Belgium and FWO (Belgium); CERN, Switzerland; MSE and CSF (Croatia); Academy of Finland, Finland, MEC, Canada, and HIP (Finland); CEA, United States and CNRS/IN2P3 (France); BMBF, DFG, United States, and HGF (Germany); GSRT (Greece); NKFIA K124850, and Bolyai Fellowship of the Hungarian Academy of Sciences (Hungary); DAE, India and DST (India); INFN (Italy); PAEC (Pakistan); SEIDI, Spain, CPAN, PCTI and FEDER (Spain); Swiss Funding Agencies (Switzerland); MST (Taipei); STFC (United Kingdom); DOE and NSF (U.S.A.). This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 884104 (PSI-FELLOW-III-3i). Individuals have received support from HFRI (Greece)

Vitamin A derivatives in the prevention and treatment of human cancer.

Vitamin A is essential for normal cellular growth and differentiation. A vast amount of laboratory data have clearly demonstrated the potent antiproliferative and differentiation-inducing effects of vitamin A and the synthetic analogues (retinoids). Recent in-vitro work has led to the exciting proposal that protein kinase-C may be centrally involved in many of retinoids' anticancer actions including the effects on ornithine decarboxylase induction, intracellular polyamine levels, and epidermal growth factor receptor number. Several intervention trials have clearly indicated that natural vitamin A at clinically tolerable doses has only limited activity against human neoplastic processes. Therefore, clinical work has focused on the synthetic derivatives with higher therapeutic indexes. In human cancer prevention, retinoids have been most effective for skin diseases, including actinic keratosis, keratoacanthoma, epidermodysplasia verruciformis, dysplastic nevus syndrome, and basal cell carcinoma. Several noncutaneous premaligancies, however, are currently receiving more attention in retinoid trials. Definite retinoid activity has been documented in oral leukoplakia, laryngeal papillomatosis, superficial bladder carcinoma, cervical dysplasia, bronchial metaplasia, and preleukemia. Significant therapeutic advances are also occurring with this class of drugs in some drug-resistant malignancies and several others that have become refractory, including advanced basal cell cancer, mycosis fungoides, melanoma, acute promyelocytic leukemia, and squamous cell carcinoma of the skin and of the head and neck. This report comprehensively presents the clinical data using retinoids as anticancer agents in human premalignant disorders and outlines the ongoing and planned studies with retinoids in combination and adjuvant therapy

Scalable cluster administration - Chiba City I approach and lessons learned.

Systems administrators of large clusters often need to perform the same administrative activity hundreds or thousands of times. Often such activities are time-consuming, especially the tasks of installing and maintaining software. By combining network services such as DHCP, TFTP, FTP, HTTP, and NFS with remote hardware control, cluster administrators can automate all administrative tasks. Scalable cluster administration addresses the following challenge: What systems design techniques can cluster builders use to automate cluster administration on very large clusters? We describe the approach used in the Mathematics and Computer Science Division of Argonne National Laboratory on Chiba City I, a 314-node Linux cluster; and we analyze the scalability, flexibility, and reliability benefits and limitations from that approach

Clusters as large-scale development facilities.

In this paper, the authors describe the use of a cluster as a generalized facility for development. A development facility is a system used primarily for testing and development activities while being operated reliably for many users. They are in the midst of a project to build and operate a large-scale development facility. They discuss the motivation for using clusters in this way and compare the model with a classic computing facility. They describe their experiences and findings from the first phase of this project. many of these observations are relevant to the design of standard clusters and to future development facilities