The Influence of Instrumental Sources of Variance on Mass Spectral Comparison Algorithms

Current search algorithms for the identification of substances based only on their electron ionization mass spectra provide the correct compound as their top result approximately 80% of the time. One contributing factor to the ~20% deviation in the first-hit recognition rate is that traditional algorithms work by comparing the unknown spectrum to an ‘ideal’ or consensus spectrum of each reference compound. The inclusion of replicate reference spectra in a database has been shown to improve the probability of ranking the correct identity in the number one position, but the variance in ion abundances caused by different conditions or different instruments remains an intractable problem and the major source of uncertainty in mass spectral identification. To assess the relative contributions of different factors to the spectral variance of replicate spectra, this study initially considered the repeller voltage, focus lens voltage, and ion energy as primary parameters. A three-factor, three-level, full-factorial design of experiments was conducted using cocaine as a model compound. A library of cocaine spectra was collected with a gas chromatography-electron ionization-mass spectrometer (GC-EI-MS) by extracting each spectrum across the eluting peak. The 20 most abundant ions in the library of cocaine spectra were extracted to assess the contribution of each instrument parameter on the variance in ion abundances by performing multivariate analysis of variance (MANOVA). Results showed that these instrument parameters were responsible for only ~3% of the total variance in the normalized abundances. This initial finding prompted a subsequent study that monitored the branching ratios of cocaine during random fluctuations in the vacuum chamber pressure. Random changes in vacuum pressure accounted for ~90% of the natural variance in the relative ion abundances of the two most abundant peaks of cocaine (not including the base peak). The database of 389 cocaine spectra was then used to compare the traditional consensus approaches to spectral matching with two variants of a novel algorithm called the Expert Algorithm for Substance Identification (EASI). EASI uses multivariate linear modeling to predict the ion abundances of 20 ions in each spectrum, assuming that each of the 20 ion abundances is continuously dependent on the other 19 ion abundances. One variant of this model includes intercepts in the linear models, and the other does not. To assess the effect of spectral variance on spectral identifications, traditional measures of spectral similarity or dissimilarity were calculated between each query spectrum and the consensus cocaine spectrum, including the Pearson product-moment correlation (PPMC) coefficients, mean absolute residuals (MARs), Euclidean distances, and NIST scores. These metrics were then used as binary classifiers to obtain true positives, true negatives, false positives, and false negatives at a range of decision thresholds. The models were tested on a database of spectra that included more than 300 cocaine spectra from different laboratories, more than 700 spectra of 5 common drugs, and 10 spectra of cocaine diastereomers: allococaine, pseudococaine, and pseudoallococaine. The EASI models outperformed the consensus approach on every metric. EASI coupled with the PPMC values, MARs and Euclidean distances had accuracies greater than 90% with zero false positives, including spectra of cocaine diastereomers and cocaine collected on different instruments. The Mahalanobis distances to the training set as a binary classifier were also reported, and they were found to be as good or better than EASI at discriminating between cocaine and non-cocaine spectra. Each measure of spectral similarity was used to build receiver operating characteristic (ROC) curves and calculate the area under the ROC curve (AUC). When taking only the cocaine diastereomers as known negatives, the EASI without a constant had the highest area under the curve (AUC=0.925), followed by EASI including a constant (AUC=0.907), and lastly the consensus model with (AUC=0.829). This work shows that random variations in vacuum pressure are responsible for most of the short-term variance in replicate mass spectra and that a model (EASI) that accounts for cross-correlations between the different fragment ions allow superior compound identification to traditional algorithms

Estudio de factibilidad para la creación de una Guardería Hotel SPA canino PUPY LOVE, ubicada en el sector norte de la ciudad de Quito, provincia de Pichincha

Determinar el macro y micro ambiente del proyecto con el objetivo de establecer el entorno en el cual se va a desarrollar.El siguiente trabajo de titulación tiene como objetivo analizar e investigar la FACTIBILIDAD PARA LA CREACIÓN DE UNA GUARDERÍA HOTEL SPA CANINO PUPPY LOVE, UBICADA EN EL SECTOR NORTE DE LA CIUDAD DE QUITO, PROVINCIA DE PICHINCHA, para cubrir la demanda y la necesidad de alojamiento de un segmento de mercado objetivo, como son las mascotas, por medio de un Diagnóstico Situacional, que permitirá determinar el Ambiente Interno y Ambiente Externo, así como los factores que pueden causar inconvenientes en el desarrollo del proyecto. También el desarrollo del Estudio de Mercado brindara un mecanismo que ayude a establecer mejoras características a la prestación del servicio. Determinar la Demanda, Oferta, demanda insatisfecha, mercado objetivo del proyecto permite que enfoquemos nuestros esfuerzos en reconocer cual es la viabilidad que tiene el trabajo de estudio y determinar la factibilidad de la creación del Hotel Spa Canino. Se estableció la organización, misión, visión y los principios y valores implementados al Hotel basándose en un estudio legal que permita la construcción y elaboración del mismo también se realizó un estudio financiero del proyecto el cual permite conocer si existe rentabilidad del mismo

Is strategic proactivity a driver of an environmental strategy? Effects of innovation and internationalization leadership

This study analyses strategic proactivity as a driving factor in the implementation of an advanced environmental strategy in a firm. Strategic proactivity is defined as a firm''s tendency to initiate voluntary changes instead of reacting to events in the environment and according to previous literature, can be interpreted as a combination of internal factors that characterise a firm''s business strategy as that of a prospector firm. In this study, we measured this through innovation, with two variables related to the firm''s entire production cycle: R&D expenditure and patents. However, we also considered two more strategic proactivity indicators: innovation proactivity and internationalisation proactivity. These two proactivity variables take into account the innovative and international actions of the firms, going beyond the actions usually taken by firms in the same sector. Using panel data methodology, we obtained results that show that firms who invest in R&D and patent their innovations achievemore advanced positions in their environmental strategies. Empirical evidence also shows that firms with a greater innovation effort throughout the production cycle (product, process, organisation and marketing) than their competitors also attain more advanced positions (proactivity) in environmental matters. In other words, innovation proactivity is a driver of environmental strategy. In relation to internationalization, the results also showed that firms that operate in a larger geographical area than their competitors adapt to the most demanding environmental legislation, placing them in a position of environmental leadership in their respective sectors. The inclusion of internationalization as an indicator of strategic proactivity, the measurement of proactivity variables and the correction of firms'' specific unobserved aspects are some of this paper''s contributions

Sistema de gestión de seguridad y salud en el trabajo para reducir accidentes laborales empresa Decor Stone S.A.C Lima 2022

La presente investigación se planteó con el propósito de determinar el sistema de gestión de seguridad y salud en el trabajo para reducir accidentes laborales. Es un estudio sustantivo, donde el tipo es aplicado, el nivel descriptivo correlacional y el diseño pre experimental, para el marco teórico citaremos a los autores Muños, Salas, Obando, Satolongo y Villa para el sistema de gestión de seguridad y salud en el trabajo y los fundamentos teóricos de Miño, Esparza, Checa y Roque para reducir accidentes laborales. Se consideró a 20 trabajadores de la sociedad, que se dedican al área de corte, traslado de material y descarga de contenedor sintetizado en el rubro de piedras naturales. Para la recolección de datos se utilizó como instrumentos el formato de matriz IPERC, formato de inspección de los EPP, formato de inspección de los extintores, formato de inspecciones internas y formato de accidentes para ambas variables, mismas que se recolectaron y procesaron en el programa SPSS, para ello se obtuvo la validez de dos expertos en la materia. Entre los resultados obtenidos se muestra que existe una correlación positiva alta, entre la variable gestión de seguridad y salud en el trabajo, obteniendo así una mejora del 93%

Evaluation of an integrated system for classification, assessment and comparison of services for long-term care in Europe: the eDESDE-LTC study

The harmonization of European health systems brings with it a need for tools to allow the standardized collection of information about medical care. A common coding system and standards for the description of services are needed to allow local data to be incorporated into evidence-informed policy, and to permit equity and mobility to be assessed. The aim of this project has been to design such a classification and a related tool for the coding of services for Long Term Care (DESDE-LTC), based on the European Service Mapping Schedule (ESMS). Methods. The development of DESDE-LTC followed an iterative process using nominal groups in 6 European countries. 54 researchers and stakeholders in health and social services contributed to this process. In order to classify services, we use the minimal organization unit or "Basic Stable Input of Care" (BSIC), coded by its principal function or "Main Type of Care" (MTC). The evaluation of the tool included an analysis of feasibility, consistency, ontology, inter-rater reliability, Boolean Factor Analysis, and a preliminary impact analysis (screening, scoping and appraisal). Results: DESDE-LTC includes an alpha-numerical coding system, a glossary and an assessment instrument for mapping and counting LTC. It shows high feasibility, consistency, inter-rater reliability and face, content and construct validity. DESDE-LTC is ontologically consistent. It is regarded by experts as useful and relevant for evidence-informed decision making. Conclusion: DESDE-LTC contributes to establishing a common terminology, taxonomy and coding of LTC services in a European context, and a standard procedure for data collection and international comparison

COVID-19 E O CALENDÁRIO ESCOLAR BRASILEIRO: MEDO E FRUSTRAÇÃO

The aim of this study was to investigate what are the emotions of teachers and students in the face of the reorganization of the school calendar that suspended the classroom instruction and replaced them with not courses, during the social isolation needed to contain the progress of Covid-19. The method adopted was Mann-Whitney statistical inference. The application of this model allows testing whether the distributions are equal in location, that is, whether one population tends to have higher values than the other, or whether they have the same median. The two populations tested were teachers and students, with a survey collecting perceptions in a questionnaire with ten emotions. The result of this research presents three different emotions: fear, sadness, and frustration. Fear is a feeling that provides a state of alert demonstrated by the fear of doing something. The sadness is defined as the act in which our power to act is reduced or contradicted. Frustration is an emotional state that accompanies the interruption of a motivated behavior, i.e., it is a psychological state that results from the blockage of motivation caused by any barrier that prevents you from achieving a project or objective expected. Considering the results, it is suggested to school managers along with the academic community, if you listen to these emotions and develop measures to counteract them, under penalty of not reaching the goal of reorganization of the school calendar

Improved collection of hematopoietic stem cells and progenitors from Fanconi anemia patients for gene therapy purposes

Anèmia de Fanconi; Mozobil; Teràpia gènicaAnemia de Fanconi; Mozobil; Terapia génicaFanconi anemia; Mozobil; Gene therapyDifficulties in the collection of hematopoietic stem and progenitor cells (HSPCs) from Fanconi anemia (FA) patients have limited the gene therapy in this disease. We have investigated (ClinicalTrials.gov, NCT02931071) the safety and efficacy of filgrastim and plerixafor for mobilization of HSPCs and collection by leukapheresis in FA patients. Nine of eleven enrolled patients mobilized beyond the threshold level of 5 CD34+ cells/μL required to initiate apheresis. A median of 21.8 CD34+ cells/μL was reached at the peak of mobilization. Significantly, the oldest patients (15 and 16 years old) were the only ones who did not reach that threshold. A median of 4.27 million CD34+ cells/kg was collected in 2 or 3 aphereses. These numbers were markedly decreased to 1.1 million CD34+ cells/kg after immunoselection, probably because of weak expression of the CD34 antigen. However, these numbers were sufficient to facilitate the engraftment of corrected HSPCs in non-conditioned patients. No procedure-associated serious adverse events were observed. Mobilization of CD34+ cells correlated with younger age, higher leukocyte counts and hemoglobin values, lower mean corpuscular volume, and higher proportion of CD34+ cells in bone marrow (BM). All these values offer crucial information for the enrollment of FA patients for gene therapy protocols.This work was supported by grants from the European Commission’s Seventh Framework Program (HEALTH-F5-2012-305421 to the EUROFANCOLEN Consortium, J.A.B., J. Sevilla, C.D.-d.-H., J. Soulier, and J. Surralles), Ministerio de Sanidad, Servicios Sociales e Igualdad (EC11/060 and EC11/550 to C.D.-d.-H., J. Sevilla, J.A.B., and J. Surralles), Ministerio de Economía, Comercio y Competitividad and Fondo Europeo de Desarrollo Regional (SAF2015-68073-R, RTI2018-097125-B-I00 to P.R. and RTI2018-098419-B-I00 to J. Surralles), Fondo de Investigaciones Sanitarias at the Instituto de Salud Carlos III (RD12/0019/0023 to J.C.S.), and Consejería de Educación, Juventud y Deporte de la Comunidad de Madrid (AvanCell Project; B2017/BMD3692). CIBERER is an initiative of the Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional. J. Surralles is supported by ICREA Academia and FARF

Silk-reinforced collagen hydrogels with raised multiscale stiffness for mesenchymal cells 3D culture

Type I collagen hydrogels are of high interest in tissue engineering. With the evolution of 3D bioprinting technologies, a high number of collagen-based scaffolds have been reported for the development of 3D cell cultures. A recent proposal was to mix collagen with silk fibroin derived from Bombyx mori silkworm. Nevertheless, due to the difficulties in the preparation and the characteristics of the protein, several problems such as phase separation and collagen denaturation appear during the procedure. Therefore, the common solution is to diminish the concentration of collagen although in that way the most biologically relevant component is reduced. In this study, we present a new, simple, and effective method to develop a collagen-silk hybrid hydrogel with high collagen concentration and with increased stiffness approaching that of natural tissues, which could be of high interest for the development of cardiac patches for myocardial regeneration and for preconditioning of mesenchymal stem cells (MSCs) to improve their therapeutic potential. Sericin in the silk was preserved by using a physical solubilizing procedure that results in a preserved fibrous structure of type I collagen, as shown by ultrastructural imaging. The macro- and micromechanical properties of the hybrid hydrogels measured by tensile stretch and atomic force microscopy, respectively, showed a more than twofold stiffening than the collagen-only hydrogels. Rheological measurements showed improved printability properties for the developed biomaterial. The suitability of the hydrogels for 3D cell culture was assessed by 3D bioprinting bone marrow-derived MSCs cultured within the scaffolds. The result was a biomaterial with improved printability characteristics that better resembled the mechanical properties of natural soft tissues while preserving biocompatibility owing to the high concentration of collagen. Impact statement In this study, we report the development of silk microfiber-reinforced type I collagen hydrogels for 3D bioprinting and cell culture. In contrast with previously reported studies, a novel physical method allowed the preservation of the silk sericin protein. Hydrogels were stable, showed no phase separation between the biomaterials, and they presented improved printability. An increase between two- and threefold of the multiscale stiffness of the scaffolds was achieved with no need of using additional crosslinkers or complex methods, which could be of high relevance for cardiac patches development and for preconditioning mesenchymal stem cells (MSCs) for therapeutic applications. We demonstrate that bone marrow-derived MSCs can be effectively bioprinted and 3D cultured within the stiffened structures.This work was supported in part by the Spanish Ministry of Sciences, Innovation and Universities (DPI2017-83721-P and PGC2018-097323-A-I00) and by the Marie Sklodowska- Curie Action, Innovative Training Networks 2018, EU Grant Agreement no. 812772.Peer ReviewedPostprint (published version

Genetic analyses of aplastic anemia and idiopathic pulmonary fibrosis patients with short telomeres, possible implication of DNA-repair genes

Aplastic anemia; DNA repair; Pulmonary fibrosisAnèmia aplàstica; Reparació d'ADN; Fibrosi pulmonarAnemia aplástica; Reparación de ADN; Fibrosis pulmonarBACKGROUND: Telomeres are nucleoprotein structures present at the terminal region of the chromosomes. Mutations in genes coding for proteins involved in telomere maintenance are causative of a number of disorders known as telomeropathies. The genetic origin of these diseases is heterogeneous and has not been determined for a significant proportion of patients. METHODS: This article describes the genetic characterization of a cohort of patients. Telomere length was determined by Southern blot and quantitative PCR. Nucleotide variants were analyzed either by high-resolution melting analysis and Sanger sequencing of selected exons or by massive sequencing of a panel of genes. RESULTS: Forty-seven patients with telomere length below the 10% of normal population, affected with three telomeropathies: dyskeratosis congenita (4), aplastic anemia (22) or pulmonary fibrosis (21) were analyzed. Eighteen of these patients presented known pathogenic or novel possibly pathogenic variants in the telomere-related genes TERT, TERC, RTEL1, CTC1 and ACD. In addition, the analyses of a panel of 188 genes related to haematological disorders indicated that a relevant proportion of the patients (up to 35%) presented rare variants in genes related to DNA repair or in genes coding for proteins involved in the resolution of complex DNA structures, that participate in telomere replication. Mutations in some of these genes are causative of several syndromes previously associated to telomere shortening. CONCLUSION: Novel variants in telomere, DNA repair and replication genes are described that might indicate the contribution of variants in these genes to the development of telomeropathies. Patients carrying variants in telomere-related genes presented worse evolution after diagnosis than the rest of patients analyzed.Funded by grants PI14–01495 and PI17–01401 (Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain supported by FEDER funds) and by one ACCI project from CIBERER and one grant to the FPI cohort from CIBERES

Permanent control of HIV-1 pathogenesis in exceptional elite controllers: a model of spontaneous cure

Elite controllers (EC) represent a small subset of HIV-1-infected people that spontaneously control viral replication. However, natural virological suppression and absence of immune dysfunction are not always long-term sustained. We define exceptional EC (EEC) as HIV-1 subjects who maintain the EC characteristics without disease progression for more than 25 years. We analyzed three EEC, diagnosed between 1988 and 1992, who never showed signs of clinical disease progression in absence of any antiretroviral treatment. A comprehensive clinical, virological, and immunological study was performed. The individuals simultaneously exhibited ≥3 described host protective alleles, low levels of total HIV-1 DNA (0.50). Inflammation levels of EEC were similar to HIV-1 negative donors. Remarkably, they showed an exceptional lack of viral evolution and 8-fold lower genetic diversity (<0.01 s/n) in env gene than other EC. We postulate that these EEC represent cases of spontaneous functional HIV-1 cure. A non-functional and non-genetically evolving viral reservoir along with an HIV-1-specific immune response seems to be key for the spontaneous functional cure.Work in Centro Nacional de Microbiologia (ISCIII) was supported by grants SAF (2016–77894-R) from Ministerio de Economia y Competitividad (MINECO) (Spain) and Fondo de Investigación Sanitaria (FIS)-Instituto de Salud CarlosIII, grant FIS (PI 13/02269, ISCIII) and in part by the RIS-RETIC grants RD12/0017/0028 and RD16CIII/0002/0005 funded by the ISCIII-FEDER. MP has a contract of RIS-RETIC RD16CIII/0002/0005. This work was supported by grants from the MINECO, FIS-Instituto de Salud CarlosIII, Fondos Europeos para el Desarrollo Regional, FEDER, grant numbers PI16/00684, PI19/01127, CPII014/00025 to ER-M. and FI14/00431 to LT-D.; the Gilead Fellowship Program (grant numbers GLD17/00299); the Red de Investigación en Sida (grant number RD16/0025/0020). ER-M. is supported by Consejería de Salud y Bienestar Social of Junta de Andalucía through the Nicolás Monardes Program (C-0032/17). Research in VS-M group was supported by Fondo de Investigación Sanitaria (FIS)-Instituto de Salud CarlosIII, grant FIS (PI 17CIII/00049). Grifols partially supported work in the AIDS Research Institute IrsiCaixa. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S