SeDeM as a Tool to Validate Drug Substance Manufacturing Processes and Assess Scalability and Suitability for Direct Compression: Supplier Screening

During the development of an oral solid form of a drug substance, a thorough understanding of the critical material attributes is necessary, as the physical properties of the active pharmaceutical ingredient (API) can profoundly influence the drug product's manufacturability, critical quality attributes, and bioavailability. The objective of this study was to validate the manufacturing process of the drug Linezolid from three different sources at both the pilot and industrial scale and to identify differences in critical material attributes between the API manufacturers. Furthermore, the scalability factor between the pilot and industrial scale and the suitability of a process for direct compression were also evaluated. In the present study, the different sources of API were characterized by SeDeM methodology, particle size distribution, and scanning electron microscopy determinations. The statistical analysis revealed that no statistically significant differences were found for any of the parameters under study for the same API source analyzed on both scales. On the other hand, for most of the parameters evaluated, statistical differences were observed between the different sources. It was concluded that SeDeM was able to successfully validate the API manufacturing process, assess scalability, and distinguish between sources. Therefore, it could be highly valuable in the formulation phase to select the best API source. Keywords: Linezolid; SeDeM expert system; critical material attribute; critical quality attribute; direct compression; drug substance manufacturers; particle size; powder characterization; preformulation; process validation

DETERMINACIÓN DE METABOLITOS DE COCAINA EN ADULTOS TRAUMATIZADOS ATENDIDOS EN UNA EMERGENCIA HOSPITALARIA

El objetivo de la investigación fue precisar la morbilidad en el consumo de cocaína en pacientes que consultan por traumatismos en la sala de emergencia del Hospital Universitario "Dr. Luis Razetti", Barcelona, Venezuela. El estudio tiene carácter prospectivo, descriptivo. Se aplicó como método el test (check drug) de detección de metabolitos de cocaína, en orina, a todos los pacientes ingresados entre junio y noviembre de 2006. Dichos pacientes fueron seleccionados con los siguientes criterios: mayores de 12 años y con traumas múltiples o politraumatizados. Todo paciente con patologías de origen no traumático, fué excluido del estudio. En el análisis estadístico se aplicaron distribuciones de frecuencias y porcentajes, regresión logística asociando morbilidad con el género y el tiempo. De los 783 pacientes pesquisados, el 82% fue de género masculino, resultando 41,3% positivos para cocaína contra solo una positividad del 7,9% en el caso del género femenino; el riesgo de resultar intoxicado en los hombres mantuvo un rango entre 2 y 8 (media = 5,22) veces mayor que para la mujeres. Aproximadamente el 70% de las lesiones fueron localizadas en la región craneal y/o torácica sin haberse determinado el nivel de severidad de la misma.   PALABRAS CLAVE: Cocaína, indicador, traumatismos, metabolitos. ABSTRACT The aim of this research was to determine the morbidity of cocaine users undergoing trauma consultation in the emergency room of the University Hospital Dr. Luis Razetti, Barcelona, Venezuela. The study is prospective and descriptive. The test method (DrugCheck) for the detection of cocaine metabolites was used for all patients admitted between June and November 2006. Patients were selected using the following criteria: 12 or more years old and with multiple traumas or polytraumatized. Patients with non-traumatic disorders were excluded from the study. The data was analyzed using frequency distributions and percentages, and a logistic regression associating disease with sex and time. Of the 783 patients evaluated, 82% were male, with 41.3% positive for cocaine compared to only 7.9% cocaine positive females. The risk of being intoxicated ranged between 2 and 8 (mean = 5.22) times higher for men than for women. Approximately 70% of the lesions were located in the cranial region and/or chest although the level of severity was unclear.   KEY WORDS: Cocaine, indicator, trauma, metabolite

Solving the large discrepancy between inclusive and exclusive measurements of the 8Li+4He→11B+n{}^8{\rm Li}+{}^4{\rm He}\to{}^{11}{\rm B}+n reaction cross section at astrophysical energies

A solution of the large discrepancy existing between inclusive and exclusive measurements of the ${}^8{\rm Li}+{}^4{\rm He}\to{}^{11}{\rm B}+n$ reaction cross section at $E_{cm} <3$ MeV is evaluated. This problem has profound astrophysical relevance for this reaction is of great interest in Big-Bang and r-process nucleosynthesis. By means of a novel technique, a comprehensive study of all existing ${}^8{\rm Li}+{}^4{\rm He}\to{}^{11}{\rm B}+n$ cross section data is carried out, setting up a consistent picture in which all the inclusive measurements provide the reliable value of the cross section. New unambiguous signatures of the strong branch pattern non-uniformities, near the threshold of higher ${}^{11}{\rm B}$ excited levels, are presented and their possible origin, in terms of the cluster structure of the involved excited states of ${}^{11}{\rm B}$ and ${}^{12}{\rm B}$ nuclei, is discussed.Comment: 5 pages, 4 figures, 1 tabl

Measurement of neutron yield by 62 MeV proton beam on a thick Beryllium target

In the framework of research on IVth generation reactors and high intensity neutron sources a low-power prototype neutron amplifier was recently proposed by INFN. It is based on a low-energy, high current proton cyclotron, whose beam, impinging on a thick Beryllium converter, produces a fast neutron spectrum. The world database on the neutron yield from thick Beryllium target in the 70 MeV proton energy domain is rather scarce. The new measurement was performed at LNS, covering a wide angular range from 0 to 150 degrees and an almost complete neutron energy interval. In this contribution the preliminary data are discussed together with the proposed ADS facility.Comment: Talk given by Mikhail Osipenko at the 11th International Conference on Nucleus-Nucleus Collisions (NN2012), San Antonio, Texas, USA, May 27-June 1, 2012. To appear in the NN2012 Proceedings in Journal of Physics: Conference Series (JPCS

On the magnitude of the 8Li + 4He → 11B + n reaction cross section at the Big-Bang temperature

n/

Mirror nuclei emission and isospin transport at intermediate energies

Isospin effects are studied in reactions induced by 40Ca projectiles at E/A=25 MeV on 40Ca, 48Ca and 46Ti targets. The N/Z of projectile-like, target-like and mid-velocity sources are probed by measuring isotopic (7Li/6Li and 9Be/7Be) and isobaric (7Li/7Be) yield ratios, for semi-peripheral events. The presence of isospin diffusion and drift phenomena is observed. It seems indeed that the interaction time between projectile and target does not allow a complete charge equilibration between quasi-projectile and quasi-target sources

Isospin Dependence of Incomplete Fusion Reactions at 25 Mev/a

40Ca+40,48Ca,46Ti reactions at 25 MeV/A have been studied using the 4p CHIMERA detector. An isospin effect on the competition between incomplete fusion and dissipative binary reaction mechanisms has been observed. The probability of producing a compound system is observed to be lower in the case of N=Z colliding systems as compared to the case of reactions induced on the more neutron rich 48Ca target. Predictions based on CoMD-II calculations show that the competition between fusion-like and dissipative reactions, for the selected centrality, can strongly constraint the parameterization of symmetry energy and its density dependence in the nuclear equation of state.Comment: 4 pages 3 figures submitted to phys.rew.Let

Study of an intrinsically safe infrastructure for training and research on nuclear technologies

Within European Partitioning & Transmutation research programs, infrastructures specifically dedicated to the study of fundamental reactor physics and engineering parameters of future fast-neutron-based reactors are very important, being some of these features not available in present zero-power prototypes. This presentation will illustrate the conceptual design of an Accelerator-Driven System with high safety standards, but ample flexibility for measurements. The design assumes as base option a 70MeV, 0.75mA proton cyclotron, as the one which will be installed at the INFN National Laboratory in Legnaro, Italy and a Beryllium target, with Helium gas as core coolant. Safety is guaranteed by limiting the thermal power to 200 kW, with a neutron multiplication coefficient around 0.94, loading the core with fuel containing Uranium enriched at 20% inserted in a solid-lead diffuser. The small decay heat can be passively removed by thermal radiation from the vessel. Such a system could be used to study, among others, some specific aspects of neutron diffusion in lead, beam-core coupling, target cooling and could serve as a training facility

Detailed stratified GWAS analysis for severe COVID-19 in four European populations

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ~0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.S.E.H. and C.A.S. partially supported genotyping through a philanthropic donation. A.F. and D.E. were supported by a grant from the German Federal Ministry of Education and COVID-19 grant Research (BMBF; ID:01KI20197); A.F., D.E. and F.D. were supported by the Deutsche Forschungsgemeinschaft Cluster of Excellence ‘Precision Medicine in Chronic Inflammation’ (EXC2167). D.E. was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the Computational Life Sciences funding concept (CompLS grant 031L0165). D.E., K.B. and S.B. acknowledge the Novo Nordisk Foundation (NNF14CC0001 and NNF17OC0027594). T.L.L., A.T. and O.Ö. were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), project numbers 279645989; 433116033; 437857095. M.W. and H.E. are supported by the German Research Foundation (DFG) through the Research Training Group 1743, ‘Genes, Environment and Inflammation’. L.V. received funding from: Ricerca Finalizzata Ministero della Salute (RF-2016-02364358), Italian Ministry of Health ‘CV PREVITAL’—strategie di prevenzione primaria cardiovascolare primaria nella popolazione italiana; The European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS- and for the project ‘REVEAL’; Fondazione IRCCS Ca’ Granda ‘Ricerca corrente’, Fondazione Sviluppo Ca’ Granda ‘Liver-BIBLE’ (PR-0391), Fondazione IRCCS Ca’ Granda ‘5permille’ ‘COVID-19 Biobank’ (RC100017A). A.B. was supported by a grant from Fondazione Cariplo to Fondazione Tettamanti: ‘Bio-banking of Covid-19 patient samples to support national and international research (Covid-Bank). This research was partly funded by an MIUR grant to the Department of Medical Sciences, under the program ‘Dipartimenti di Eccellenza 2018–2022’. This study makes use of data generated by the GCAT-Genomes for Life. Cohort study of the Genomes of Catalonia, Fundació IGTP (The Institute for Health Science Research Germans Trias i Pujol) IGTP is part of the CERCA Program/Generalitat de Catalunya. GCAT is supported by Acción de Dinamización del ISCIII-MINECO and the Ministry of Health of the Generalitat of Catalunya (ADE 10/00026); the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (2017-SGR 529). M.M. received research funding from grant PI19/00335 Acción Estratégica en Salud, integrated in the Spanish National RDI Plan and financed by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (European Regional Development Fund (FEDER)-Una manera de hacer Europa’). B.C. is supported by national grants PI18/01512. X.F. is supported by the VEIS project (001-P-001647) (co-funded by the European Regional Development Fund (ERDF), ‘A way to build Europe’). Additional data included in this study were obtained in part by the COVICAT Study Group (Cohort Covid de Catalunya) supported by IsGlobal and IGTP, European Institute of Innovation & Technology (EIT), a body of the European Union, COVID-19 Rapid Response activity 73A and SR20-01024 La Caixa Foundation. A.J. and S.M. were supported by the Spanish Ministry of Economy and Competitiveness (grant numbers: PSE-010000-2006-6 and IPT-010000-2010-36). A.J. was also supported by national grant PI17/00019 from the Acción Estratégica en Salud (ISCIII) and the European Regional Development Fund (FEDER). The Basque Biobank, a hospital-related platform that also involves all Osakidetza health centres, the Basque government’s Department of Health and Onkologikoa, is operated by the Basque Foundation for Health Innovation and Research-BIOEF. M.C. received Grants BFU2016-77244-R and PID2019-107836RB-I00 funded by the Agencia Estatal de Investigación (AEI, Spain) and the European Regional Development Fund (FEDER, EU). M.R.G., J.A.H., R.G.D. and D.M.M. are supported by the ‘Spanish Ministry of Economy, Innovation and Competition, the Instituto de Salud Carlos III’ (PI19/01404, PI16/01842, PI19/00589, PI17/00535 and GLD19/00100) and by the Andalussian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018, COVID-Premed, COVID GWAs). The position held by Itziar de Rojas Salarich is funded by grant FI20/00215, PFIS Contratos Predoctorales de Formación en Investigación en Salud. Enrique Calderón’s team is supported by CIBER of Epidemiology and Public Health (CIBERESP), ‘Instituto de Salud Carlos III’. J.C.H. reports grants from Research Council of Norway grant no 312780 during the conduct of the study. E.S. reports grants from Research Council of Norway grant no. 312769. The BioMaterialBank Nord is supported by the German Center for Lung Research (DZL), Airway Research Center North (ARCN). The BioMaterialBank Nord is member of popgen 2.0 network (P2N). P.K. Bergisch Gladbach, Germany and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. He is supported by the German Federal Ministry of Education and Research (BMBF). O.A.C. is supported by the German Federal Ministry of Research and Education and is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy—CECAD, EXC 2030–390661388. The COMRI cohort is funded by Technical University of Munich, Munich, Germany. This work was supported by grants of the Rolf M. Schwiete Stiftung, the Saarland University, BMBF and The States of Saarland and Lower Saxony. K.U.L. is supported by the German Research Foundation (DFG, LU-1944/3-1). Genotyping for the BoSCO study is funded by the Institute of Human Genetics, University Hospital Bonn. F.H. was supported by the Bavarian State Ministry for Science and Arts. Part of the genotyping was supported by a grant to A.R. from the German Federal Ministry of Education and Research (BMBF, grant: 01ED1619A, European Alzheimer DNA BioBank, EADB) within the context of the EU Joint Programme—Neurodegenerative Disease Research (JPND). Additional funding was derived from the German Research Foundation (DFG) grant: RA 1971/6-1 to A.R. P.R. is supported by the DFG (CCGA Sequencing Centre and DFG ExC2167 PMI and by SH state funds for COVID19 research). F.T. is supported by the Clinician Scientist Program of the Deutsche Forschungsgemeinschaft Cluster of Excellence ‘Precision Medicine in Chronic Inflammation’ (EXC2167). C.L. and J.H. are supported by the German Center for Infection Research (DZIF). T.B., M.M.B., O.W. und A.H. are supported by the Stiftung Universitätsmedizin Essen. M.A.-H. was supported by Juan de la Cierva Incorporacion program, grant IJC2018-035131-I funded by MCIN/AEI/10.13039/501100011033. E.C.S. is supported by the Deutsche Forschungsgemeinschaft (DFG; SCHU 2419/2-1).Peer reviewe