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Data de publicació electrònica: 02-05-2023 Objectives: To identify prognostic models which estimate the risk of critical COVID-19 in hospitalized patients and to assess their validation properties. Study design and setting: We conducted a systematic review in Medline (up to January 2021) of studies developing or updating a model that estimated the risk of critical COVID-19, defined as death, admission to intensive care unit, and/or use of mechanical ventilation during admission. Models were validated in two datasets with different backgrounds (HM [private Spanish hospital network], n = 1,753, and ICS [public Catalan health system], n = 1,104), by assessing discrimination (area under the curve [AUC]) and calibration (plots). Results: We validated 18 prognostic models. Discrimination was good in nine of them (AUCs ≥ 80%) and higher in those predicting mortality (AUCs 65%-87%) than those predicting intensive care unit admission or a composite outcome (AUCs 53%-78%). Calibration was poor in all models providing outcome's probabilities and good in four models providing a point-based score. These four models used mortality as outcome and included age, oxygen saturation, and C-reactive protein among their predictors. Conclusion: The validity of models predicting critical COVID-19 by using only routinely collected predictors is variable. Four models showed good discrimination and calibration when externally validated and are recommended for their use.

The European EPI-CT study aims to quantify cancer risks from CT examinations of children and young adults. Here, we assess the risk of brain cancer.We pooled data from nine European countries for this cohort study. Eligible participants had at least one CT examination before age 22 years documented between 1977 and 2014, had no previous diagnosis of cancer or benign brain tumour, and were alive and cancer-free at least 5 years after the first CT. Participants were identified through the Radiology Information System in 276 hospitals. Participants were linked with national or regional registries of cancer and vital status, and eligible cases were patients with brain cancers according to WHO International Classification of Diseases for Oncology. Gliomas were analysed separately to all brain cancers. Organ doses were reconstructed using historical machine settings and a large sample of CT images. Excess relative risks (ERRs) of brain cancer per 100 mGy of cumulative brain dose were calculated with linear dose-response modelling. The outcome was the first reported diagnosis of brain cancer after an exclusion period of 5 years after the first electronically recorded CT examination.We identified 948 174 individuals, of whom 658 752 (69%) were eligible for our study. 368 721 (56%) of 658 752 participants were male and 290 031 (44%) were female. During a median follow-up of 5·6 years (IQR 2·4-10·1), 165 brain cancers occurred, including 121 (73%) gliomas. Mean cumulative brain dose, lagged by 5 years, was 47·4 mGy (SD 60·9) among all individuals and 76·0 mGy (100·1) among people with brain cancer. A significant linear dose-response relationship was observed for all brain cancers (ERR per 100 mGy 1·27 [95% CI 0·51-2·69]) and for gliomas separately (ERR per 100 mGy 1·11 [0·36-2·59]). Results were robust when the start of follow-up was delayed beyond 5 years and when participants with possibly previously unreported cancers were excluded.The observed significant dose-response relationship between CT-related radiation exposure and brain cancer in this large, multicentre study with individual dose evaluation emphasises careful justification of paediatric CTs and use of doses as low as reasonably possible.EU FP7; Belgian Cancer Registry; La Ligue contre le Cancer, L'Institut National du Cancer, France; Ministry of Health, Labour and Welfare of Japan; German Federal Ministry of Education and Research; Worldwide Cancer Research; Dutch Cancer Society; Research Council of Norway; Consejo de Seguridad Nuclear, Generalitat de Catalunya, Spain; US National Cancer Institute; UK National Institute for Health Research; Public Health England.

The approval of nusinersen for the treatment of spinal muscular atrophy (SMA) has significantly changed the natural history of the disease. Nevertheless, scoliosis secondary to axial muscle weakness occurs at some point in most of patients with SMA and a conventional posterior interlaminar approach for intrathecal administration of nusinersen can be particularly challenging to perform in patients with severe scoliosis and/or previous spine fusion surgeries. We developed a protocol for the administration of nusinersen in pediatric patients, which includes a decision-tree algorithm that categorizes patients according to the estimated technical difficulty for the intrathecal administration. Complex spine patients were defined as those with a Cobb angle greater than 50° and/or a history of spinal surgery, while the rest of patients were considered non-complex. Nusinersen was successfully administered through a conventional non-CT-guided lumbar puncture in all 14 non-complex spine patients (110 out of 110 procedures; 100%). The feasibility of the intrathecal injection in the 15 complex spine patients was assessed by 3D CT. Administration was considered unfeasible in 7 out of these 15 patients according to imaging. In the 8 complex spine patients in whom the administration was considered feasible, conventional non-CT-guided lumbar punctures were successful only in 19 out of 53 procedures (36%). The remaining 34 procedures (64%) were guided by CT scan, all successful. Our work demonstrates that a cut-off point of 50° in Cobb angle and history of spinal surgery can reliably be used to anticipate the need for CT guidance in nusinersen administration.

The potential effect of gestational exposure to phthalates on the lung function levels during childhood is unclear. Therefore, we examined this association at different ages (from 4 to 11 years) and over the whole childhood. Specifically, we measured 9 phthalate metabolites (MEP, MiBP, MnBP, MCMHP, MBzP, MEHHP, MEOHP, MECPP, MEHP) in the urine of 641 gestating women from the INMA study (Spain) and the forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and FEV1/FVC in their offspring at ages 4, 7, 9 and 11. We used linear regression and mixed linear regression with a random intercept for subject to assess the association between phthalates and lung function at each study visit and for the overall childhood, respectively. We also assessed the phthalate metabolites mixture effect on lung function using a Weighted Quantile Sum (WQS) regression. We observed that the phthalate metabolites gestational levels were consistently associated with lower FVC and FEV1 at all ages, both when assessed individually and jointly as a mixture, although most associations were not statistically significant. Of note, a 10% increase in MiBP was related to lower FVC (-0.02 (-0.04, 0)) and FEV1 z-scores (-0.02 (-0.04,-0.01) at age 4. Similar significant reductions in FVC were observed at ages 4 and 7 associated with an increase in MEP and MnBP, respectively, and for FEV1 at age 4 associated with an increase in MBzP. WQS regression consistently identified MBzP as an important contributor to the phthalate mixture effect. We can conclude that the gestational exposure to phthalates was associated with children's lower FVC and FEV1, especially in early childhood, and in a statistically significant manner for MEP, MiBP, MBzP and MnBP. Given the ubiquity of phthalate exposure and its established endocrine disrupting effects in children, our findings support current regulations that limit phthalate exposure. The INMA study was funded by grants from the European Union (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1) , and from Spain: Instituto de Salud Carlos III and Ministry of Health (Red INMA G03/176; CB06/02/0041; PI041436, PI081151, PI06/0867, PS09/00090, PI13/02187; FIS-FEDER: PI03/1615, PI04/1509, PI04/1112, PI04/1931, PI05/1079, PI05/1052, PI06/1213, PI07/0314, PI09/02647, PI11/01007, PI11/02591, PI11/02038, PI12/01890, PI13/1944, PI13/2032, PI14/00891, PI14/1687, PI17/01194, and PI17/00663; MV16/00015; predoctoral grant PFIS - FI14/00099, pre-doctoral grant PFIS FIS-FSE: 17/00260, FIS19/1338, MV16/00015, Miguel Servet-FEDER: CP11/0178, and Miguel Servet-FSE: MS13/00054, MSII16/00051, and MS16/00128) , CIBERESP; Department of Health of the Basque Government (2005111093 and 2009111069) ; the Provincial Government of Gipuzkoa (DFG06/004 and DFG08/001) ; and the Generalitat de Catalunya-CIRIT (1999SGR 00241) . ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. We acknowledge support from the Spanish Ministry of Science and Innovation through the "Centro de Excelencia Severo Ochoa 2019-2023" Program (CEX 2018-000806-S) , and support from the Generalitat de Catalunya through the CERCA Program.

The potential effect of gestational exposure to phthalates on the lung function levels during childhood is unclear. Therefore, we examined this association at different ages (from 4 to 11 years) and over the whole childhood. Specifically, we measured 9 phthalate metabolites (MEP, MiBP, MnBP, MCMHP, MBzP, MEHHP, MEOHP, MECPP, MEHP) in the urine of 641 gestating women from the INMA study (Spain) and the forced vital capacity (FVC), forced expiratory volume in 1 s (FEV(1)) and FEV(1)/FVC in their offspring at ages 4, 7, 9 and 11. We used linear regression and mixed linear regression with a random intercept for subject to assess the association between phthalates and lung function at each study visit and for the overall childhood, respectively. We also assessed the phthalate metabolites mixture effect on lung function using a Weighted Quantile Sum (WQS) regression. We observed that the phthalate metabolites gestational levels were consistently associated with lower FVC and FEV(1) at all ages, both when assessed individually and jointly as a mixture, although most associations were not statistically significant. Of note, a 10% increase in MiBP was related to lower FVC (-0.02 (-0.04, 0)) and FEV(1) z-scores (-0.02 (-0.04, -0.01) at age 4. Similar significant reductions in FVC were observed at ages 4 and 7 associated with an increase in MEP and MnBP, respectively, and for FEV(1) at age 4 associated with an increase in MBzP. WQS regression consistently identified MBzP as an important contributor to the phthalate mixture effect. We can conclude that the gestational exposure to phthalates was associated with children's lower FVC and FEV(1), especially in early childhood, and in a statistically significant manner for MEP, MiBP, MBzP and MnBP. Given the ubiquity of phthalate exposure and its established endocrine disrupting effects in children, our findings support current regulations that limit phthalate exposure.

Resumen Objetivo Evaluar el nivel de implementacion de los protocolos asociados a la prevencion de la debilidad muscular adquirida en la unidad de cuidados intensivos (UCI), asi como la presencia del fisioterapeuta en distintas UCI de Espana. Metodo Estudio descriptivo, transversal realizado en 86 UCI de adultos de Espana entre los meses de marzo a junio de 2017. Se excluyeron UCI neuroquirurgicas y de grandes quemados. Se utilizo encuesta multirrespuesta que incluia preguntas sobre los protocolos de: control de glucemia, sedacion, valoracion del dolor, prevencion del delirium, manejo del delirium y movilizacion precoz. La encuesta fue rellenada a traves de un aplicativo protegido por usuario y contrasena. Analisis inferencial con t de Student o U de Mann-Whitney y de correlacion con Pearson o Rho de Spearman. Resultados El 89,5% de las UCI tenian protocolo de control de glucemia, con rango predominante de 110-140 mg/dl. El 74,4% evaluaban el nivel de sedacion, si bien solo tenian protocolos de sedacion el 36% de ellas. Con relacion a la valoracion del dolor se realizaba en el 73,7% de los pacientes comunicativos, mientras que en los no comunicativos solo era del 47,5%. Solo el 37,2% realizaban screening diario para detectar el delirium, y disponian de protocolos de prevencion del delirium el 31,4% de las UCI, del manejo del delirium el 26,7% y de movilizacion precoz el 14% de las UCI. En el 34,9% de los casos se solicita interconsulta al servicio de rehabilitacion. Conclusiones La implementacion de los diferentes protocolos asociados a la prevencion de la debilidad muscular adquirida ha sido elevada en relacion con los protocolos de control de glucemia, valoracion del nivel de sedacion y del dolor de pacientes comunicativos, mientras que baja en los de movilizacion precoz y screening y prevencion del delirio. Asimismo, es poco frecuente la presencia del fisioterapeuta en la UCI.

The approval of nusinersen for the treatment of spinal muscular atrophy (SMA) has significantly changed the natural history of the disease. Nevertheless, scoliosis secondary to axial muscle weakness occurs at some point in most of patients with SMA and a conventional posterior interlaminar approach for intrathecal administration of nusinersen can be particularly challenging to perform in patients with severe scoliosis and/or previous spine fusion surgeries. We developed a protocol for the administration of nusinersen in pediatric patients, which includes a decision-tree algorithm that categorizes patients according to the estimated technical difficulty for the intrathecal administration. Complex spine patients were defined as those with a Cobb angle greater than 50 degrees and/or a history of spinal surgery, while the rest of patients were considered non-complex. Nusinersen was successfully administered through a conventional non-CT-guided lumbar puncture in all 14 non-complex spine patients (110 out of 110 procedures; 100%). The feasibility of the intrathecal injection in the 15 complex spine patients was assessed by 3D CT. Administration was considered unfeasible in 7 out of these 15 patients according to imaging. In the 8 complex spine patients in whom the administration was considered feasible, conventional non-CT-guided lumbar punctures were successful only in 19 out of 53 procedures (36%). The remaining 34 procedures (64%) were guided by CT scan, all successful. Our work demonstrates that a cutoff point of 50 degrees in Cobb angle and history of spinal surgery can reliably be used to anticipate the need for CT guidance in nusinersen administration. (C) 2021 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Capturing complexity is both a conceptual and a practical challenge in palliative care. The HexCom model has proved to be an instrument with strong reliability and valid for describing the needs and strengths of patients in home care. In order to explore whether it is also perceived to be helpful in enhancing coordinated and patient-centered care at a practical level, a methodological study was carried out to assess the face validity of the model. Particularly, a Delphi method involving a group of 15 experts representing the full spectrum of healthcare professionals involved in palliative care was carried out. The results show that there is a high level of agreement, with a Content Validity Index-Item greater than 0.92 both with regard to the complexity model and the HexCom-Red, HexCom-Basic and HexCom-Clin instruments, and higher than 0.85 regarding the HexCom-Figure and the HexCom-Patient instruments. This consensus confirms that the HexCom model and the different instruments that are derived from it are valued as useful tools for a broad range of healthcare professional in coordinately capturing of complexity in healthcare practice.

The wish to hasten death has been little researched in the area of Mediterranean countries and we are not aware of specific studies on its particularities in home care in our setting. The aim of this work was to investigate the prevalence and evolution of wish to hasten death in home care, analysing its relationship with physical, emotional, spiritual, ethical and social-family unrest.Longitudinal observational study in palliative home care in Catalonia. 43 teams agreed on the level of complexity after the first visit and after the discharge of the patient with the HexCom model, which classifies the desire to anticipate death into Low complexity (no or sporadic manifestation); Medium (persistent desire that requires specific treatment); or High (persistent desire that is considered potentially refractory). For the comparison of proportions, Pearson's Chi-squared test was used and a multivariate logistic regression analysis was performed, in which the dependent variable corresponded to the desire to hasten initial death. The level of significance was p≤0.05.The total number of patients included in this study was 1,677, of whom 1,169 (69.7%) were oncologic. The prevalence of desire to hasten death was 6.67%. It was related to spiritual distress, especially lack of meaning (OR 3.25) and lack of connection (OR 3.81), to psychoemotional distress (OR 2.34) and to ethical distress. Protective factors were spiritual distress in relation to transcendence (OR 0.50), the caregiver being a partner (OR 0.50) and being cared for by a team that included psychology and social work (OR 0.34). The desire to anticipate death is stable in 71.6% of patients.The desire to anticipate death is a changing and complex phenomenon that can emerge at any time. The presence of psycho-emotional, spiritual-existential and ethical discomfort, especially in patients without a partner, should make us take a proactive attitude to identify it early.El deseo de adelantar la muerte ha sido poco investigado en el área de los países mediterráneos y no conocemos estudios específicos sobre sus particularidades en atención domiciliaria en nuestro entorno. El objetivo de este trabajo fue investigar la prevalencia y la evolución del deseo de anticipar la muerte en atención domiciliaria, analizando su relación con el malestar físico, emocional, espiritual, ético y sociofamiliar.Estudio observacional longitudinal en el ámbito de la atención domiciliaria paliativa en Catalunya. 43 equipos acordaron el nivel de complejidad tras la primera visita y tras el alta del paciente con el modelo HexCom, el cual clasifica el deseo de anticipar la muerte en complejidad Baja (manifestación nula o esporádica); Media (Deseo persistente que requiere tratamiento específico); o Alta (Deseo persistente que se considera potencialmente refractario). Para la comparación de proporciones se utilizó la prueba de Ji cuadrado de Pearson y se realizó un análisis de regresión logística multivariante, en el que la variable dependiente correspondía con el deseo de adelantar la muerte inicial. El nivel de significación fue p≤0,05.El número total de pacientes incluidos en este estudio fue de 1.677, de los cuales 1.169 (69,7%) eran oncológicos. La prevalencia de deseo de anticipar la muerte fue del 6,67%. Se relacionó con el malestar espiritual, ante todo con la falta de sentido (OR 3,25) y de conexión (OR 3,81), con el malestar psicoemocional (OR 2,34) y con el malestar ético. Fueron factores protectores el malestar espiritual en relación con la transcendencia (OR 0,50), que el cuidador fuese la pareja (OR 0,50) y ser atendido por un equipo en el que se incluyese psicología y trabajo social (OR 0,34). El deseo de anticipar la muerte fue estable en el 71,6% de los pacientes.El deseo de anticipar la muerte es un fenómeno cambiante y complejo que puede emerger en cualquier momento. La presencia de malestar psicoemocional, espiritual-existencial y ético, sobre todo en pacientes sin pareja, nos han de hacer tomar una actitud proactiva para identificarlo precozmente.

International audience; Within the European Epidemiological Study to Quantify Risks for Paediatric Computerized Tomography (EPI-CT study), a cohort was assembled comprising nearly one million children, adolescents and young adults who received over 1.4 million computed tomography (CT) examinations before 22 years of age in nine European countries from the late 1970s to 2014. Here we describe the methods used for, and the results of, organ dose estimations from CT scanning for the EPI-CT cohort members. Data on CT machine settings were obtained from national surveys, questionnaire data, and the Digital Imaging and Communications in Medicine (DICOM) headers of 437,249 individual CT scans. Exposure characteristics were reconstructed for patients within specific age groups who received scans of the same body region, based on categories of machines with common technology used over the time period in each of the 276 participating hospitals. A carefully designed method for assessing uncertainty combined with the National Cancer Institute Dosimetry System for CT (NCICT, a CT organ dose calculator), was employed to estimate absorbed dose to individual organs for each CT scan received. The two-dimensional Monte Carlo sampling method, which maintains a separation of shared and unshared error, allowed us to characterize uncertainty both on individual doses as well as for the entire cohort dose distribution. Provided here are summaries of estimated doses from CT imaging per scan and per examination, as well as the overall distribution of estimated doses in the cohort. Doses are provided for five selected tissues (active bone marrow, brain, eye lens, thyroid and female breasts), by body region (i.e., head, chest, abdomen/pelvis), patient age, and time period (1977-1990, 1991-2000, 2001-2014). Relatively high doses were received by the brain from head CTs in the early 1990s, with individual mean doses (mean of 200 simulated values) of up to 66 mGy per scan. Optimization strategies implemented since the late 1990s have resulted in an overall decrease in doses over time, especially at young ages. In chest CTs, active bone marrow doses dropped from over 15 mGy prior to 1991 to approximately 5 mGy per scan after 2001. Our findings illustrate patterns of age-specific doses and their temporal changes, and provide suitable dose estimates for radiation-induced risk estimation in epidemiological studies.

Knowledge on the environmental determinants of physical activity in COPD is scarce and no information on the specific role of air pollution is available. We aimed to explore the association between air pollution and physical activity in COPD patients, hypothesizing that higher levels of air pollution may negatively impact on physical activity. This is a cross-sectional analysis of baseline pre-randomisation data from the multi-centre Urban Training study (NCT01897298) in Catalonia. We estimated annual residential averages of nitrogen dioxide (NO2) and particulate matter (PM2.5, PM10 and PM2.5absorbance) using land-use regression models. We assessed physical activity (daily step count and sedentary time) using the Dynaport MoveMonitor, and physical activity experience using the C-PPAC difficulty score. We built mixed-effect linear regression models for each outcome and exposure, adjusting for confounders with a random intercept for the city area. We included 407 patients (mean (SD) 69 (8) y, 85% male, FEV1 57% pred); median (p25-p75) levels of air pollutants were at the WHO health limits (NO2 43.5 µg/m3 [35.0-48.7]; PM2.5 12.6 µg/m3 [10.7-13.8]; PM10 24.9 µg/m3 [22.3-27.7]). Multi-variable analysis showed an association between NO2 and sedentary time (Coef=0.23 [95% CI 0.03, 0.43] per IQR change, p=0.027) and C-PPAC difficulty (-2.57 [-5.12, -0.02] per IQR change, p=0.048). No other significant associations were observed. In COPD patients, higher NO2 levels of residential areas are associated with increased sedentary times and the experience of increased difficulty during physical activity. This likely contributes to the negative effects of air pollution in COPD patients and requires further investigation.

A new hybrid diffuse optical platform was developed with fast, time-resolved and correlation spectroscopied. We present the device and results from an on-going clinical trial to evaluate hemodynamic and metabolic biomarkers for guiding acute ischemic stroke management.

Background Intensive care unit–acquired muscle weakness (ICUAW) has an incidence of 40–46%. Early mobilisation is known to be a protective factor. Objective The aim of the study was to identify the incidence of ICUAW in Spain and to evaluate variables likely to contribute to the development of ICUAW. Methods A 4-month, prospective observational multicentre cohort study was conducted on patients receiving invasive mechanical ventilation for at least 48 h. Data were collected from ICU day 3 until ICU discharge. The primary outcome was presence of ICUAW (diagnosed using the Medical Research Council [MRC] scale). The secondary outcome was nurse–patient ratio, physiotherapist availability, analgesia, sedation and delirium management, glycaemic control, and daily level of mobility during the ICU stay as per the ICU Mobility Scale. A logistic regression model was constructed based exclusively on days 3–5 of the ICU stay. Results The data of 642 patients were analysed from 80 ICUs, accounting for 35% of all ICUs in Spain. The incidence of ICUAW was 58% (275 of 474 patients; 95% confidence interval [CI] [53–62]). The predictors for ICUAW were older age (odds ratio [OR] = 1.01; 95% CI [1.00–1.03]) and more days with renal replacement therapy (OR = 1.01; 95% CI [1.00–1.02]). The protective factors for ICUAW were male gender (OR = 0.58; 95% CI [0.38–0.89]), higher Barthel Index (showing prehospital functional independence) (OR = 0.97; 95% CI [0.95–0.99]), more days of being awake and cooperative (defined by a feasible MRC assessment) (OR = 0.98; 95% CI [0.97–0.99]), presence of delirium (OR = 0.98; 95% CI [0.97–0.99]), and more days with active mobilisation (ICU Mobility Scale ≥ 4) (OR = 0.98; 95% CI [0.97–0.99]). Conclusions The risk factors for ICUAW were functional dependence before admission, female gender, older age, and more days on renal replacement therapy. The protective factors for ICUAW were feasibility of MRC assessment, the presence of delirium, and being actively mobilised during the first 5 days in the ICU.

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Física Teórica. Fecha de lectura: 26-06-2019, This thesis, presented in the form of a "compilation of articles", touches different areas of Theoretical Physics. The first part, which comprises the first two articles, focuses on using applied holography to study out-of-equilibrium physics. More specifically, in the first article we study quantum processes called quenches and we show, by holographically constructing gravitational dual backgrounds, the way to implement a quantum quench with a real change in the hamiltonian in a Lorentz-invariant manner. The second article is framed under the theory of anomalous transport. The object of study is the gravitational contribution to the chiral anomaly, which through the chiral magnetic effect induces an energy current proportional to the square of the temperature when the system is in equilibrium. In this framework, we implement holographic quantum quenches to bring the system out of equilibrium, where no temperature can be well defined. Our results indicate a strong suppression of this effect when the system is very far from equilibrium. The second part of the thesis lies in the context of exact, non-linear general relativity. In the third article, we characterize generic, non-expanding black hole horizons and study the effect of supertranslations on them. We present a freely specifiable data set which is both necessary and sufficient to reconstruct the full horizon geometry and is composed of objects that are invariant under supertranslations. Therefore we conclude that these transformations do not transform the geometry of the horizon and should be regarded as pure gauge., Esta tesis, presentada en la forma de "compilación de artículos", toca diferentes areas de la Física Teórica. La primera parte, que consta de los dos primeros artículos, se centra en usar holografía aplicada al estudio de la física fuera del equilibrio. Más concretamente, en el primer artículo estudiamos procesos cuánticos llamados quenches y demostramos, construyendo holográficamente los escenarios gravitacionales de la teoría dual, la manera de implementar un quench cuántico con un cambio real en el hamiltoniano de manera invariante Lorentz. El segundo artículo se encuadra bajo la teoría de transporte anómalo. El objeto de estudio es la contribución gravitacional a la anomalía quiral, que a través del efecto magnético quiral induce una corriente de energía que es proporcional al cuadrado de la temperatura cuando el sistema está en equilibrio. En este escenario implementamos quenches holográficos para llevar al sistema fuera del equilibrio, donde la temperatura no está bien definida. Nuestros resultados indican una fuerte supresión de este efecto cuando el sistema está lejos de encontrarse en equilibrio. La segunda parte de esta tesis se encuentra en el contexto de la relatividad general exacta y no-lineal. En el tercer artículo, caracterizamos horizontes genéricos y que no se expanden de agujeros negros, y estudiamos el efecto que tienen las supertraslaciones en ellos. Presentamos un conjunto de datos que pueden especificarse libremente, que son necesarios y suficientes para reconstruir la geometría completa del horizonte y que son invariante bajo supertraslaciones. Por lo tanto concluimos que estas transformaciones no transforman la geometría del horizonte y deben ser consideradas como puro gauge.

Background: CT scan is a life-saving medical diagnostic tool, entailing higher levels of ionising radiation exposure than conventional radiography, which may result in an increase in cancer risk, particularly in children. Information about the use and potential health effects of CT scan imaging among young people in Spain is scarce. Objective: This paper aims to estimate the number of radiation-related cancer cases which can be expected due to the use of CT scanning in Spanish children and young adults in a single year (2013). Methods: The 2013 distribution of number and types of CT scans performed in young people was obtained for Catalonia and extrapolated to the whole Spain. Organ doses were estimated based on the technical characteristics of 17,406 CT examinations extracted from radiology records. Age and sex-specific data on cancer incidence and life tables were obtained for the Spanish population. Age and sex-specific risk models developed by the Committee on Health Risks of Exposure to Low Levels of Ionizing Radiations (BEIR VII) and Berrington de Gonzalez were used, together, with the dose estimates to derive the lifetime attributable risks of cancer in Spain due to one year of CT scanning and project the number of future cancer cases to be expected. Results: In 2013, 105,802 CT scans were estimated to have been performed in people younger than age 21. It was estimated that a total of 168.6 cancer cases (95% CrI: 30.1–421.1) will arise over life due to the ionising radiation exposure received during these CTs. Lifetime attributable risks per 100,000 exposed patients were highest for breast and lung cancer. The largest proportion of CTs was to the head and neck and hence the highest numbers of projected cancer cases were of thyroid and oral cavity/pharynx. Conclusions: Despite the undeniable medical effectiveness of CT scans, this risk assessment suggests a small excess in cancer cases which underlines the need for justification and optimisation in paediatric scanning. Given the intrinsic uncertainties of these risk projection exercises, care should be taken when interpreting the predicted risks. Keywords: CT scan, Risk, Cancer, Young population, Ionising radiation

Recent publications reported that children in disadvantaged areas undergo more CT scanning than others. The present study is aimed to assess the potential differences in CT imaging by socioeconomic status (SES) in Spanish young scanned subjects and if such differences vary with different indicators or different time point SES measurements. The associations between CT scanning and SES, and between the CT scan rate per patient and SES were investigated in the Spanish EPI-CT subcohort. Various SES indicators were studied to determine whether particular SES dimensions were more closely related to the probability of undergoing one or multiple CTs. Comparisons were made with indices based on 2001 and 2011 censuses. We found evidence of socio-economic variation among young people, mainly related to autonomous communities of residence. A slightly higher rate of scans per patient of multiple body parts in the less affluent categories was observed, possibly reflecting a higher rate of accidents and violence in these groups. The number of CT scans per patient was higher both in the most affluent and the most deprived categories and somewhat lower in the intermediate groups. This relation varied with the SES indicator used, with lower CT scans per patients in categories of high unemployment and temporary work, but not depending on categories of unskilled work or illiteracy. The relationship between these indicators and number of CTs in 2011 was different than that seen with the 2001 census, with the number of CTs increasing with higher unemployment. Overall we observed some differences in the SES distribution of scanned patients by Autonomous Community in Spain. There was, however, no major differences in the frequency of CT scans per patient by SES overall, based on the 2001 census. The use of different indicators and of SES data collected at different time points led to different relations between SES and frequency of CT scans, outlining the difficulty of adequately capturing the social and economic dimensions which may affect health and health service utilisation.

Marc Bosch de Doria, alcalde de Dosrius.

L’homme est depositaire du capital genetique du vivant et represente une espece dans la lignee evolutive. Mais l’espece humaine innove. Au lieu de s’adapter au milieu, elle l’a adapte a ses exigences et c’est la seule espece qui est capable d’influencer son evolution. Durant la premiere periode de sa vie, developpement et maturite sexuelle, l’homme s’inscrit dans le processus evolutif en transmettant son capital genetique et en elevant sa progeniture ; la seconde periode n’a pas de finalite apparente. Cette periode comprend le vieillissement – un processus propre a l’humain – et dans cette perspective pourrait se comprendre comme le fruit d’une adaptation au nouvel environnement que l’homme s’est cree. Au cours du vieillissement, le potentiel cerebral sculpte durant la periode de developpement et de maturite, optimalise la structuration de l’espece humaine dans le temps socio-culturel. Cette structuration est d’abord individuelle, car chaque individu est caracterise par la specificite de l’information qu’il porte, mais elle est aussi collective, car a chaque generation, la connaissance doit etre partagee. Cette structuration est favorisee par la coexistence, au sein d’une meme population, d’individus d’âges tres diversifies, porteurs d’informations a des etats differents de maturation.

The present thesis introduces the EPI-CT cohort study; a European collaborative effort aimed at quantifying the health risks of computed tomography (CT scan) radiation exposure during childhood and assesses the main epidemiological factors that could bias the risk estimates in similar studies. It confirms an increase in the CT scan usage among patients younger than 21 years in Catalonia during the period 1991-2013. Of importance is that, the results obtained within the Spanish branch of the EPI-CT study do not suggest that the number of CT scans per person differ among the socioeconomic spectrum. This thesis also includes a health risk assessment of the 2013 Spanish CT imaging practice in young population, which projects 0.2% additional cancer cases (over the spontaneously arising cancer cases) to occur in the expected lifespan of the CT scan exposed individuals. A very initial analysis quantifying the association between the cumulative organ-doses and leukaemia and brain cancer mortality is included, suggesting a dose-related increase in the risk of brain tumours and leukaemia mortality., Aquesta tesi presenta l'estudi de cohort EPI-CT; un estudi Europeu adreçat a la quantificació dels riscos per a la salut associats a l'exposició a la radiació de la tomografia computaritzada (TC) durant la infància i avalua els principals factors epidemiològics que podrien esbiaixar les estimacions de risc en estudis similars. Aquesta tesi confirma un augment en l'ús de la TC en pacients menors de 21 anys a Catalunya durant el període 1991-2013 i alhora, conclou que el nombre de TCs per persona no difereix segons el nivell socioeconòmic del pacient, suggerint un ús similar en tota la població. Aquesta tesi inclou també una avaluació del risc per a la salut de totes les TCs que es van dur a terme al 2013 en població jove a Espanya, i projecta un increment d’un 0,2% de càncers respecte als que s’esperen que ocorrin de forma espontànea entre la població exposada. S’inclou també una anàlisi molt inicial en la que s’observa una associació entre dosi a nivell d’òrgan i mortalitat per leucèmia i càncer de cervell.

International audience; •The multinational EPI-CT study was set-up in 2011 to provide direct estimates of risk of solid tumours and leukaemia among children and young adults who underwent computed tomography (CT) scanning and to consolidate the scientific basis for optimization of paediatric CT protocols and patient protection.•Under a common protocol, cohort studies were conducted in Belgium, Denmark, France, Germany, the Netherlands, Norway, Spain, Sweden and the United Kingdom, coordinated by the International Agency for Research on Cancer (IARC). •The study recruited a total of about 950,000 patients having undergone at least one CT-scan before the age of 22 years. A total of 8.7 million person-years of incidence follow-up were accrued between 1977 and 2014. Cohort members were followed up passively through linkage with population-based cancer and mortality registries. A methodology was developed to reconstruct individual organ doses and estimate associated uncertainties, using data available in electronic archiving systems of the radiology departments of participating hospitals. Description of the cohort and analysis of mortality risk are presented here.•Proposals for possible collaboration in further analyses of the data should be addressed to Dr. Ausrele Kesminiene (KesmienieneA@visitors.iarc.fr) and will be reviewed by the EPI-CT steering committee

The specific structure of the blood-brain barrier (BBB) is based on the partnership of brain endothelial cells and astrocytes. In the last decade, cocultures of these two cell types have been developed as in vitro models. However, these studies did not allow close contacts between both cell types. We report here a syngenic coculture model using rat endothelial cells on one side of a polyethylene terephtalate filter and rat astrocytes on the other. Endothelial cells retain their typical morphology and are factor VIII and OX 26 positive. We optimized the diameter of the membrane pores to establish very close contacts between the cells through the membrane pores without mixing the two cell types. Transmission electron microscopy showed evidence of tight junction formation between the endothelial cells and few pinocytic vesicles. The cocultures reached high electrical resistances up to 1000 Omegacm(2) showing their ability to limit the passage of ions. A 15-fold increase in gamma-glutamyl transpeptidase activity was measured in the endothelial cells in coculture compared to endothelial cell monoculture. Our syngenic coculture represents a useful in vitro model of the rat BBB that may prove to be valuable for studying the passage of substances across the barrier as well as other aspects of the BBB function.

Recently, patterned polystyrene surfaces containing hydrophobic (PS) and more hydrophilic (PSox) areas have been shown to be capable of directing cellular growth, which is mainly due to the competitive adsorption of adhesive and antiadhesive molecules. In this article, the competitive adsorption between a pluronic surfactant and fibronectin was studied on homogeneous PS or PSox substrates conditioned with mixtures containing increasing concentrations of one of the two molecules. Radiolabeling and X-ray photoelectron spectroscopy techniques showed that fibronectin adsorption increased on both surfaces if the fibronectin concentrations increased in the conditioning mixture. In contrast, fibronectin adsorption decreased on PSox and did not occur on PS surfaces when pluronic concentrations increased in the coating mixture. A comparison of these data with pheochromocytoma and Schwann cells cultured on patterned surfaces showed that the direction of cell growth on PSox areas depended first on the relative concentrations of the two components in the mixtures, and second, on their ratio; the best concentration ratio probably depends on the cell's ability to recondition its support.

Adult rats were treated by intraperitoneal injection of aluminum gluconate for 3 months. Rats were submitted to the radial maze test to determine the influence of chronic aluminum intoxication on cognitive and noncognitive behavioral processes. Both learning abilities (working memory and reference memory) and rapidity (time spent to respond and to master a trial) were analyzed. Aluminum concentration was evaluated in the brain, serum, and liver to assess aluminum body burden. While hippocampus and neocortex showed a significant increase in aluminum concentration, aluminum treatment did never affect the animal's performance during cue learning or when the insert cues were removed. The only behavioral difference observed was a decrease in rapidity: both the total time to finish a trial and the latency to make the first choice were lengthened in aluminum-intoxicated rats.

Background: Computed tomography (CT) has great clinical utility and its usage has increased dramatically over the last few decades. Serious concerns have been raised about the potential cancer risk...

Background and Aims: Medical ionizing radiation represents an indispensable tool in modern medicine and it is the largest human-made source of radiation exposure. At moderate to high doses, ionisin...

We have developed a protocol for the production and longterm storage of polyethylene glycol (PEG) sections for immunocytochemistry. Sections obtained by this protocol allow immunolabeling for many different antigens, such as intermediate filaments, macrophage markers, or neurotransmitter enzymes. Standard histological staining can also be performed on these sections. This fixation-embedding system may therefore be of interest for histopathology of rare specimens, as well as for experimental research. Multiple labeling can be performed either on the same section or on consecutive thin sections, thus allowing a more thorough analysis of precious experimental material. We compare the advantages of PEG vs cryostat or vibratome sections. This protocol has been used to study the inactivation of antigenicity by paraffin embedding. We have identified the infiltration by paraffin as the antigenicity inactivating step, not dehydration or high temperature as generally thought.

Axonal regeneration of septal cholinergic neurons was examined after lesion of the septohippocampal pathway of the adult rat and implantation of tubes containing peripheral cellular or acellular substrates. After empty tube implantation, no regenerated structures were observed in the conduit. However, after implanting tubes filled with sections of predegenerated sciatic nerves or a fibrin-fibronectin-containing matrix provided by peripheral regeneration chambers, numerous regenerated axons were detected 6 weeks after the operation. At the electron microscopic level, regenerated axons were observed in the grafted sciatic nerves in contact with Schwann cells but also in contact with astrocytes which were able to migrate and send processes into the graft. After fibrin-fibronectin-containing-matrix implantation, the regenerated structure between septum and hippocampus was composed mainly of fibroblasts, astrocytes, and regenerated axons associated to these central glial cells.

Previous studies investigating associations between occupational history and risk of exocrine pancreatic cancer (EPC) did not use biomarkers of exposure. The only two studies that measured internal concentrations of organochlorine compounds (OCs) in EPC did not analyse their relationship with occupation.To analyse the relationship between occupational history and blood concentrations of seven OCs in patients with EPC.Incident cases of EPC were prospectively identified, and during hospital admission were interviewed face-to-face on occupational history and life-style factors (n = 135). Occupations were coded according to the International Standard of Occupations 1988. Some occupational exposures were also assessed with the Finnish job-exposure matrix (Finjem). Serum concentrations of OCs were analysed by high-resolution gas chromatography with electron-capture detection.Craftsmen and related trades workers had significantly higher concentrations of polychlorinated biphenyl (PCB) congeners 138, 153 and 180. Years worked in agriculture did not influence concentrations of p,p'-DDT, p,p'-DDE, hexachlorobenzene or β-hexachlorocyclohexane. Subjects who ever worked in agriculture had lower concentrations of PCBs (all p0.05). Occupational exposure to lead, nickel and low frequency magnetic fields was significantly associated with higher concentrations of PCBs.Certain occupations were associated with higher concentrations of PCBs, suggesting that these compounds may account for some increased risks found in previous studies. The lack of association between work in agriculture and concentrations of OC pesticides is consistent with occupation playing a lesser role than diet in influencing OC concentrations. Occupational studies on the relationships among exposure to industrial agents and EPC risk may need to consider adjusting for exposure to PCBs.

In order to investigate whether a fibrin-fibronectin-containing matrix of a peripheral regeneration chamber could promote the growth of central nervous system neurons, hippocampal and septal slices were co-cultured in the presence of this acellular substrate. In introducing the peripheral matrix into a 2-mm-long tube between hippocampal and septal slices, a spatio-temporal sequence of cell migration and axonal growth was described by light and electron microscopy. Axons were able to elongate directly into the flocculent material constituting the matrix and a possible neurite-promoting activity was implicated in this process as axonal growth was not detected in direct contact with rat plasma coagulated with calcium, or chicken plasma coagulated with thrombin, used as control matrices. However, in the 3 different substrates tested, astrocytes were able to migrate and dilated astroglial processes containing intermediate filaments were detected. Axonal processes were observed growing on the glial cell surface. GFAP-positive phagocytic cells, that could be of the same origin as astrocytes, were involved in matrix removing. Neuronal growth and glial migration arose from hippocampal and septum slices and acetylcholinesterase-containing fibers were seen in the bridging structure suggesting that cholinergic axons were able to progress to the hippocampal slice. This technique appeared to provide a model in which axonal growth and cell migration can be studied 'in vitro' in a 3-dimensional environment.

The relationships between social factors and body concentrations of environmental chemical agents are unknown in many human populations. Some chemical compounds may play an etiopathogenic role in pancreatic cancer.To analyze the relationships between occupational social class and serum concentrations of seven selected organochlorine compounds (OCs) in exocrine pancreatic cancer: dichlorodiphenyltrichloroethane (p,p'-DDT), dichlorodiphenyldichloroethene (p,p'-DDE), 3 polychlorinated biphenyls (PCBs), hexachlorobenzene, and beta-hexachlorocyclohexane.Incident cases of exocrine pancreatic cancer were prospectively identified, and interviewed face-to-face during hospital admission (n=135). Serum concentrations of OCs were analyzed by high-resolution gas chromatography with electron-capture detection. Social class was classified according to occupation.Multivariate-adjusted concentrations of all seven compounds were higher in occupational social classes IV-V (the less affluent) than in classes I-II; they were higher as well in class III than in classes I-II for four compounds. Concentrations of six OCs were higher in manual workers than in non-manual workers (p0.05 for PCBs). Social class explained statistically between 3.7% and 5.7% of the variability in concentrations of PCBs, and 2% or less variability in the other OCs.Concentrations of most OCs were higher in the less affluent occupational social classes. In pancreatic cancer the putative causal role of these persistent organic pollutants may not be independent of social class. There is a need to integrate evidence on the contribution of different social processes and environmental chemical exposures to the etiology of pancreatic and other cancers.

Sectioned rat sciatic nerves were placed in tubes to study the regrowth of injured nerve processes. First, we characterized quantitatively the regeneration of myelinated fibers at different levels of an acrylic semipermeable tube, from two to 27 weeks postoperatively. From the fifth week, myelinated fiber counts at mid-tube level were equal to the value of an intact nerve, but at the distal part the number of fibers exceeded both mid-tube level and unsectioned nerve values. At the proximal part of the tube an important fiber disorganization was observed. Second, we have compared acrylic semipermeable and totally impermeable silicone tubes at four and 27 weeks postoperatively. In terms of the number of myelinated fibers and the surface of the endoneurium at the mid-tube level, the most effective tube was the impermeable one. This study points out the importance of the tube wall permeability in nerve regeneration.

Definition of Al toxicity is traditionally presented in terms of neurone injury and glial cells are generally relagated to a secondary role involving reactive or suportive responses. However, the observations of the present work point out the astrocyte population as a potential target for Al toxic action. In vivo, significant increase in glutamine concentration was observed during aging and after Al exposure in brain regions characterized by Al accumulation, the hippocampus and the neocortex. In vitro, exposure of astrocytes to Al significantly increased GS activity. Some steps of glutamate metabolism appeared therefore to increase in the brain of rats after Al exposure.