Cortical activity disorganization and neurocognitive outcome in patients with schizophrenia and their first-degree relatives

[ES]A pesar de los grandes esfuerzos realizados durante las últimas décadas en la investigación de la esquizofrenia, aún hoy día existen numerosos interrogantes en cuanto a su sustrato neurobiológico, lo que impide la completa comprensión de su neurofisiopatología subyacente. Concretamente, muchos de los avances realizados en los últimos años apuntan no tanto hacia un problema neurológico bien localizado, sino hacia una disfunción cerebral más generalizada y ampliamente distribuida. En este sentido, el correcto equilibrio de la actividad neural oscilatoria y su sincronización, especialmente en bandas de alta frecuencia como gamma, tiene probablemente mucho que decir en cuanto a la organización de las redes corticales y, en última instancia, el funcionamiento cognitivo básico y superior. La descoordinación de la actividad neural de alta frecuencia es compatible con varios modelos etiopatológicos de la esquizofrenia: 1) un síndrome de desconexión que se remonta a etapas tempranas en los procesos del neurodesarrollo; 2) alteraciones neuroanatómicas y en varios sistemas de neurotransmisión, especialmente en las vías GABAérgicas de interneuronas inhibitorias; y 3) una prominente disfunción de la integración neural que podría parcialmente subyacer a su expresión clínica. Una forma de medir la desorganización de la actividad neural oscilatoria es mediante el parámetro de potencia ruido o ruido cortical. Esta medida se refiere básicamente a la actividad electroencefalográfica (EEG) fuera de fase o no relacionada con la estimulación externa y comprendería la actividad procedente de otros procesos corticales independientes de la tarea. Según datos previos, la desorganización de la actividad neural en alta frecuencia en esquizofrenia se caracteriza por una falta de desactivación en aquellas áreas previamente activadas en reposo en detrimento de aquellas otras regiones vinculadas a la eficiente ejecución de la tarea. Por lo tanto, es esperable que los pacientes con esquizofrenia presenten un exceso generalizado de actividad gamma, que además estaría vinculado a un peor rendimiento cognitivo y a una mayor sintomatología psicótica. Dada la alta contribución génica tanto a la actividad oscilatoria como al desarrollo de la propia enfermedad, es de esperar que estas alteraciones estén presentes en familiares sanos de pacientes con esquizofrenia y/o vinculadas a variaciones genéticas de riesgo, tales como aquellas en los genes de la neuregulina, que a su vez probablemente son clave para el desarrollo de la transmisión inhibitoria. En el presente trabajo se reclutó una muestra de 53 pacientes con esquizofrenia, 30 de los cuales sólo habían recibido un mínimo tratamiento farmacológico (primeros episodios o pacientes libres de medicación en su reclutamiento que fueron clínicamente estabilizados a corto plazo mediante una dosis mínima de haloperidol para su evaluación neurofisiológica y neuropsicológica). Asimismo, en el estudio también participaron 24 familiares de pacientes con esquizofrenia y 27 controles sanos. Se valoró en los participantes la sintomatología clínica (Positive and Negative Syndrome Scale; PANSS), la cognición (Brief Assessment of Cognition in Schizophrenia; BACS) y diversos parámetros neurofisiológicos (P3a, P3b y ruido cortical en la banda de frecuencia gamma) a través de un paradigma odd-ball (de estímulo diana inesperado). Se realizaron análisis estadísticos de componentes factoriales de la actividad ruido, de contraste intergrupal y de regresión entre las distintas variables, y de predicción de la condición de paciente a partir del parámetro de ruido cortical. Nuestros resultados dieron evidencia de que el ruido cortical en banda gamma: 1) se distribuye de forma coherente con la red modo por defecto (RMD) a lo cual cabe añadir un importante factor de actividad frontal-lateral; 2) se muestra mayor en pacientes de esquizofrenia para el factor RMD; 3) es mayor para el factor frontal en aquellos pacientes que tienen un déficit significativo en las funciones cognitivas con mayor procesamiento frontal (memoria de trabajo y resolución de problemas); 4) Correlaciona de forma inversa en el factor frontal con el rendimiento en resolución de problemas; y 5) se comporta como el mejor predictor del diagnóstico de esquizofrenia cuando es medido como factor RMD. El estudio del grupo de familiares sanos de pacientes con esquizofrenia y de las condiciones de riesgo para las tres variantes genéticas de la neuregulina ofreció resultados negativos en todo caso. Tampoco se encontraron evidencias significativas de que el origen de las alteraciones en ruido cortical gamma en nuestros pacientes se debiera a otros factores como la medicación psicótica o el artefacto muscular/ocular. Como conclusión, nuestros pacientes con esquizofrenia parecen tener un estado de hiperactivación cortical que podría corresponder a la RMD dada su distribución topográfica. Asimismo, un exceso de activación en la región frontal-lateral, pero no en la RMD, caracteriza a aquellos pacientes que sufren de un déficit cognitivo en las dimensiones con mayor carga frontal. Estos resultados se podrían interpretar como una condición de hiperexcitación cortical común a todos los pacientes de esquizofrenia en las regiones frontales-mediales y parietales-laterales. Adicionalmente, una extensión de tal hiperactivación a las regiones frontales-laterales sería característica de aquellos pacientes con peor rendimiento cognitivo de tipo frontal, lo que podría constituir una base etiológica diferenciada dentro del habitual síndrome de la esquizofrenia. Estos resultados son compatibles con modelos precedentes que interpretan esta enfermedad en clave de una organización ineficiente de la actividad cortical o que entienden una alta variabilidad en su sustrato neurobiológico. El estudio de familiares sanos y de las variantes de riesgo para la neuregulina no demostró un vínculo hereditario/genético entre la expresión de la actividad ruido gamma y la propia enfermedad. Estos resultados no permiten confirmar al exceso de ruido cortical gamma como endofenotipo para la esquizofrenia. Sin embargo, limitaciones tales como el tamaño de las muestras de familiares y de los participantes con genotipado tampoco nos permiten descartar esta hipótesis a expensas de su confirmación en futuros trabajos.[EN]Despite the great efforts made over the past decades in schizophrenia research , today there are many questions regarding its neurobiological substrate, which prevents complete understanding of its underlying neurophysiopathology . Specifically , many of the advances made ​​in recent years point to a not so well localized neurological problem , but to a more general and widespread cerebral dysfunction. In this sense, the right balance of neural oscillatory activity and its synchronization, especially in high frequency bands as gamma , probably has a lot to say about the organization of cortical networks and , ultimately , the basic cognitive functioning and top . The lack of coordination of neural activity high frequency etiopathologic supports multiple models of schizophrenia : 1 ) disconnection syndrome dating back to early neurodevelopmental processes , 2) and neuroanatomical alterations in several neurotransmitter systems , especially in GABAergic inhibitory interneurons roads , and 3) a leading neural dysfunction integration may partially underlie the clinical expression . One way to measure the disorganization of neural oscillatory activity is through the power noise parameter or cortical noise. This measure refers basically to electroencephalographic activity (EEG ) out of phase or not related to external stimulation and understand the activity from other cortical processes independent of the task. According to previous data , disruption of neural activity at high frequency in schizophrenia is characterized by a lack of deactivation in areas previously activated at rest at the expense of those other regions linked to the efficient execution of the task. Therefore, it is expected that patients with schizophrenia present generalized excess gamma activity , also be linked to a worse cognitive performance and greater psychotic symptoms . Given the high genetic contribution to both oscillatory activity and the development of the disease itself, it is expected that these alterations are present in healthy relatives of patients with schizophrenia and / or related to genetic variations of risk , such as those in genes neuregulin , which in turn is probably key to the development of inhibitory transmission . In this study a sample of 53 patients with schizophrenia were recruited , 30 of whom had received only minimal pharmacological treatment ( first episode or medication-free patients in their recruitment were clinically stabilized by a short-term low doses of haloperidol for neurophysiological and neuropsychological their ) evaluation. Furthermore , the study also included 24 relatives of patients with schizophrenia and 27 healthy controls. , Cognition ( Brief Assessment of Cognition in Schizophrenia ; BACS ) clinical symptoms (PANSS Positive and Negative Syndrome Scale) was assessed in participants and various neurophysiological parameters ( P3a , P3b and cortical noise in the gamma frequency band ) through an odd -ball paradigm ( unexpected target stimulus ) . Statistical analysis of components of the noise factor activity, and regression intergroup contrast between different variables were performed , and prediction of patient status from cortical noise parameter . Our results provide evidence that cortical gamma -band noise : 1 ) spreads consistent with the default mode ( RMD ) to which must be added an important factor front-side network activity , 2) it shows higher in patients schizophrenia for the RMD factor 3) is greater for the frontal factor in patients with significant deficits in cognitive functions more frontal processing (working memory and problem solving ), 4) correlates inversely with the factor front with performance in problem solving , and 5 ) behaves as the best predictor of the diagnosis of schizophrenia when measured as RMD factor . The study group of healthy relatives of patients with schizophrenia and the risk conditions for the three genetic variants of neuregulin gave negative results in all cases . No significant evidence that the origin of the alterations in cortical gamma noise in our patients was due to other factors such as psychotic medication or muscle / ocular artifact found. In conclusion, our patients with schizophrenia seem to have a state of cortical hyperactivation that could correspond to the RMD given its topographic distribution . Furthermore, excessive activation in the front-side but not in the RMD area characterizes those patients suffering from a cognitive deficit in dimensions greater front loading . These results could be interpreted as a condition of cortical hyperarousal common to all schizophrenia patients in the frontal - parietal - medial and lateral regions . Additionally , an extension of such hyperactivation - side frontal regions would be characteristic of patients with worse cognitive performance of the frontal type , which could be a distinct etiological basis within the usual syndrome of schizophrenia. These results are compatible with previous models that interpret key disease in an inefficient organization of cortical activity or understand high variability in neurobiological substrate . The study of healthy relatives and the risk variants for neuregulin showed no hereditary / genetic link between the expression of gamma activity noise and the disease itself. These results do not confirm the excess noise cortical gamma as endophenotypes for schizophrenia. However, limitations such as sample size and family of participants with genotyping not allow us to rule out this hypothesis at the expense of his confirmation in future studies

Entrevista a un profesional sanitario: estudio piloto de una actividad de contacto asistencial temprano en el grado en Medicina durante la pandemia por COVID-19

Introducción. El Espacio Europeo de Educación Superior fomenta el diseño y la aplicación de metodologías docentes innovadoras, que en las ciencias de la salud pueden contribuir al conocimiento y el contacto temprano con la práctica asistencial, y a la humanización de la medicina. El objetivo es presentar las características y los resultados obtenidos en la actividad grupal ‘Entrevista a un profesional sanitario’. Sujetos y métodos. La actividad se ha desarrollado en la asignatura de Psicología, de segundo curso del grado en Medicina, durante el curso académico 2019-2020 (n = 164 estudiantes; 29,3% hombres; edad media = 19,7 años). La pandemia por COVID-19 requirió su adaptación a la docencia no presencial. De los 33 profesionales sanitarios colaboradores, 29 contestaron al cuestionario de satisfacción en línea (65,5% hombres; edad media = 49,2 años). Resultados. Se constituyeron 33 grupos de estudiantes y la media (desviación estándar) de la calificación fue 8,8 (0,65) sobre 10 puntos. Los estudiantes presentaron una amplia variedad de cuestiones relacionadas con la humanización de la medicina. Las entrevistas se realizaron fundamentalmente por videoconferencia (58,6%). Los profesionales sanitarios que contestaron al cuestionario fueron preferentemente titulados en Medicina (89,7%) y especialistas en medicina familiar y comunitaria (27,6%). Presentaron una elevada satisfacción tanto en la organización de la actividad como en su valoración –media sobre 5 puntos (desviación estándar), 4,5 (0,5) y 4,7 (0,3), respectivamente–. Conclusión. ‘Entrevista a un profesional sanitario’ es una actividad grupal que facilita el contacto asistencial temprano y el papel activo de los estudiantes, ha sido muy bien valorada por los profesionales sanitarios participantes y puede adaptarse a la docencia no presencial. Palabras clave. Educación a distancia. Educación médica de pregrado. Entrevista. Método docente. Profesional sanitario. Psicología médica

Event-related potentials associated to N-back test performance in schizophrenia

Producción CientíficaMapping of Event-Related Potentials (ERP) associated with auditory and visual odd-ball paradigms has shown consistent differences between healthy controls and schizophrenia patients. It may be hypothesized that higher task attentional/cognitive demand will result in larger differences in these paradigms, which may help understanding the substrates of cognitive deficits in this syndrome. To this aim, we performed an EEG study comparing the effects of increasing the attentional/cognitive load of an auditory N-back task on the Event-Related Potential in 50 subjects with schizophrenia (11 first episodes) and 35 healthy controls. We considered a post-target window of 1000 ms to explore possible between groups differences in N100, P300, and Late Slow Wave (LSW), and compared these components between 0-back (‘lower attentional/cognitive load) and 1-back (‘higher attentional/cognitive load’) conditions. Our results showed that N100 and LSW amplitude increase from 0- to 1-back condition was significantly larger in healthy controls compared to schizophrenia patients. Furthermore, LSW amplitude difference between 0- and 1-back conditions positively correlated with performance in the behavioral cognitive assessment. Taken together, these results support that higher task attentional/cognitive load (0-back vs. 1-back condition) increase N100 amplitude differences and reveal new findings related to the LSW component in schizophrenia.Junta de Castilla y León (project VA057P17)Instituto de Salud Carlos III (project PI18/00178

Analysis of the functional EEG network in an Ecuadorian schizophrenia sample

Background and objectives Higher mental functions depend on global functional coordination of the brain. Our aim was to study the baseline condition and modulation of functional networks in a previously unevaluated clinical population, compare the results with a population from another country, and analyze their relationship with cognitive functioning. Methods We evaluated the functioning of brain networks by EEG in 24 patients with schizophrenia and 32 healthy Ecuadorian controls. EEG recordings were made at rest and while performing a P300 task. Small world (SW), Path Length (PL), clustering coefficient (CLC) and connective strength (CS) values were calculated in both conditions. The values obtained were compared between groups, with the results of Spanish patients, and the relationship between the connective parameters and the cognitive performance of the participants was analyzed. Results Higher PL, CLC and CS values were identified in patients diagnosed with schizophrenia compared to controls (in basal condition) and lower SW values in this same condition. Ecuadorian patients obtained higher values than Spanish patients in the PL and CLC parameters and lower values for the SW parameter, despite these differences, the pattern of alteration in both samples followed the same trend. Finally, the alteration of CS, SW, CLC and PL parameters at baseline was related to cognitive performance. Conclusion The connective alterations identified in Ecuadorian schizophrenic patients are consistent with those found in another sample with different genetic, environmental and cultural conditions. In addition, these alterations were associated with worse performance in different cognitive domains

Relation between EEG resting-state power and modulation of P300 task-related activity in theta band in schizophrenia

Producción CientíficaThere is some consistency in previous EEG findings that patients with schizophrenia have increased resting-state cortical activity. Furthermore, in previous work, we have provided evidence that there is a deficit in the modulation of bioelectrical activity during the performance of a P300 task in schizophrenia. Our hypothesis here is that a basal hyperactivation would be related with altered ability to change or modulate cortical activity during a cognitive task. However, no study so far, to the best of our knowledge, has studied the association between resting-state activity and task-related modulation. With this aim, we used a dual EEG paradigm (resting state and oddball task for elicitation of the P300 evoked potential) in a sample of patients with schizophrenia (n = 100), which included a subgroup of patients with first episode psychosis (n = 30), as well as a group of healthy controls (n = 93). The study measures were absolute power for resting-state; and spectral entropy (SE) and connectivity strength (CS) for P300-task data, whose modulation had been previously found to be altered in schizophrenia. Following the literature on P300, we focused our study on the theta frequency band. As expected, our results showed an increase in resting state activity and altered task-related modulation. Moreover, we found an inverse relationship between the amount of resting-state activity and modulation of task-related activity. Our results confirm our hypothesis and support the idea that a greater amount of resting theta-band synchrony could hamper the modulation of signal regularity (quantified by SE) and activity density (measured by CS) during the P300 task performance. This association was found in both patients and controls, suggesting the existence of a common mechanism and a possible ceiling effect in schizophrenia patients in relation to a decreased inhibitory function that limits their cortical reactivity to the task

Real-life outcomes in biotypes of psychotic disorders based on neurocognitive performance

Producción CientíficaAiming at discerning potential biotypes within the psychotic syndrome, we have recently reported the possible existence of two clusters or biotypes across schizophrenia and bipolar disorder characterized by their cognitive performance using the Brief Assessment of Cognition in Schizophrenia (BACS) instrument and validated with independent biological and clinical indexes (Fernández-Linsenbarth et al. in Schizophr Res 229:102–111, 2021). In this previous work, the group with larger cognitive deficits (N = 93, including 69 chronic schizophrenia, 17 first episodes (FE) of schizophrenia and 7 bipolar disorder patients) showed smaller thalamus and hippocampus volume and hyper-synchronic electroencephalogram than the group with milder deficits (N = 105, including 58 chronic schizophrenia, 25 FE and 22 bipolar disorder patients). We predicted that if these biotypes indeed corresponded to different cognitive and biological substrates, their adaptation to real life would be different. To this end, in the present work we have followed up the patients’ population included in that work at 1st and 3rd years after the date of inclusion in the 2021 study and we report on the statistical comparisons of each clinical and real-life outcomes between them. The first cluster, with larger cognitive deficits and more severe biological alterations, showed during that period a decreased capacity for job tenure (1st and 3rd years), more admissions to a psychiatric ward (1st year) and a higher likelihood for quitting psychiatric follow-up (3rd year). Patients in the second cluster, with moderate cognitive deficits, were less compliant with prescribed treatment at the 3rd year. The differences in real-life outcomes may give additional external validity to that yielded by biological measurements to the described biotypes based on neurocognition.Instituto de Salud Carlos III (grant ID PI18/00178)Dirección Regional de Salud de Castilla y León (grant ID GRS 2121/A/2020)Junta de Castilla y León - predoctoral grants from the Consejería de Educación and the European Social Fund (grant IDs VA-183-18 to IFL and VA- 223-19 to RMBRS)Publicación en abierto financiada por el Consorcio de Bibliotecas Universitarias de Castilla y León (BUCLE), con cargo al Programa Operativo 2014ES16RFOP009 FEDER 2014-2020 DE CASTILLA Y LEÓN, Actuación:20007-CL - Apoyo Consorcio BUCL

Use of schizophrenia and bipolar disorder polygenic risk scores to identify psychotic disorders

BACKGROUND: There is increasing evidence for shared genetic susceptibility between schizophrenia and bipolar disorder. Although genetic variants only convey subtle increases in risk individually, their combination into a polygenic risk score constitutes a strong disease predictor.AimsTo investigate whether schizophrenia and bipolar disorder polygenic risk scores can distinguish people with broadly defined psychosis and their unaffected relatives from controls. METHOD: Using the latest Psychiatric Genomics Consortium data, we calculated schizophrenia and bipolar disorder polygenic risk scores for 1168 people with psychosis, 552 unaffected relatives and 1472 controls. RESULTS: Patients with broadly defined psychosis had dramatic increases in schizophrenia and bipolar polygenic risk scores, as did their relatives, albeit to a lesser degree. However, the accuracy of predictive models was modest. CONCLUSIONS: Although polygenic risk scores are not ready for clinical use, it is hoped that as they are refined they could help towards risk reduction advice and early interventions for psychosis.Declaration of interestR.M.M. has received honoraria for lectures from Janssen, Lundbeck, Lilly, Otsuka and Sunovian.Funding: This work was funded by the Medical Research Council (G0901310), the Wellcome Trust (grants 085475/B/08/Z, 085475/Z/08/Z), the European Union’s Seventh Framework Programme for research, technological development and demonstration (grant 602450). This study was also supported by the NIHR Biomedical Research Centre at University College London (mental health theme) and by the NIHR Biomedical Research Centre at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry – Kings College London. Further support: NHIR Academic Clinical fellowship awarded to M.S.C.. E.B. acknowledges research funding from: BMA Margaret Temple grants 2016 and 2006, MRC – Korean Health Industry Development Institute Partnering Award (MC_PC_16014), MRC New Investigator Award and a MRC Centenary Award (G0901310), National Institute of Health Research UK post-doctoral fellowship, the Psychiatry Research Trust, the Schizophrenia Research Fund, the Brain and Behaviour Research foundation’s NARSAD Young Investigator Awards 2005, 2008, Wellcome Trust Research Training Fellowship and the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry Kings College London. The Brain and Behaviour Research foundation’s (NARSAD’s) Young Investigator Award (Grant 22604, awarded to C.I.). The BMA Margaret Temple grant 2016 to J. H.T. European Research Council Marie Curie award to A.D.-R. The infrastructure for the GROUP consortium is funded through the Geestkracht programme of the Dutch Health Research Council (ZON-MW, grant number 10-000-1001), and matching funds from participating pharmaceutical companies (Lundbeck, AstraZeneca, Eli Lilly, Janssen Cilag) and universities and mental healthcare organisations. Amsterdam: Academic Psychiatric Centre of the Academic Medical Center and the mental health institutions: GGZ Ingeest, Arkin, Dijk en Duin, GGZ Rivierduinen, Erasmus Medical Centre, GGZ Noord Holland Noord. Maastricht: Maastricht University Medical Centre and the mental health institutions: GGZ Eindhoven en de kempen, GGZ Breburg, GGZ Oost-Brabant, Vincent van Gogh voor Geestelijke Gezondheid, Mondriaan Zorggroep, Prins Clauscentrum Sittard, RIAGG Roermond, Universitair Centrum Sint-Jozef Kortenberg, CAPRI University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt, OPZ Rekem. Groningen: University Medical Center Groningen and the mental health institutions: Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGNet Warnsveld, Yulius Dordrecht and Parnassia psychomedical center (The Hague). Utrecht: University Medical Center Utrecht and the mental health institutions Altrecht, GGZ Centraal, Riagg Amersfoort and Delta. The sample from Spain was collected at the Hospital Universitario Marqués de Valdecilla, University of Cantabria, Santander, Spain, under the following grant support: Carlos III Health Institute PI020499, PI050427, PI060507, Plan Nacional de Drugs Research Grant 2005- Orden sco/3246/2004, SENY Fundació Research Grant CI 2005-0308007 and Fundación Marqués de Valdecilla API07/011. The present data were obtained at the Hospital Marqués de Valdecilla, University of Cantabria, Santander, Spain, under the following grant support: MINECO Exp.: SAF2013-46292-R

Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study

The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.This work was supported by the Medical Research Council (G0901310) and the Wellcome Trust (grants 085475/B/08/Z, 085475/Z/08/Z). This study was supported by the NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London and by the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust at King’s College London. Further support to EB: Mental Health Research UK’s John Grace QC award, BMA Margaret Temple grants 2016 and 2006, MRC—Korean Health Industry Development Institute Partnering Award (MC_PC_16014), MRC New Investigator Award and a MRC Centenary Award (G0901310), National Institute of Health Research UK post-doctoral fellowship, the Psychiatry Research Trust, the Schizophrenia Research Fund, the Brain and Behaviour Research foundation’s NARSAD Young Investigator Awards 2005, 2008, Wellcome Trust Research Training Fellowship, the NIHR Biomedical Research Centre at UCLH, and the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry King’s College London. Further support to co-authors: The Brain and Behaviour Research foundation’s (NARSAD’s) Young Investigator Award (Grant 22604, awarded to CI). The BMA Margaret Temple grant 2016 to JT. A 2014 European Research Council Marie Curie award to A Díez-Revuelta. HI has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 747429. A Medical Research Council doctoral studentship to JH-S, IA-Z and AB. A Mental Health Research UK studentship to RM. VB is supported by a Wellcome Trust Seed Award in Science (200589/Z/16/Z). FWO Senior Clinical Fellowship to RvW. The infrastructure for the GROUP consortium is funded through the Geestkracht programme of the Dutch Health Research Council (ZON-MW, grant number 10-000-1001), and matching funds from participating pharmaceutical companies (Lundbeck, AstraZeneca, Eli Lilly, Janssen Cilag) and universities and mental health care organisations (Amsterdam: Academic Psychiatric Centre of the Academic Medical Centre and the mental health institutions: GGZ Ingeest, Arkin, Dijk en Duin, GGZ Rivierduinen, Erasmus Medical Centre, GGZ Noord Holland Noord. Groningen: University Medical Centre Groningen and the mental health institutions: Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGNet Warnsveld, Yulius Dordrecht and Parnassia psycho-medical centre The Hague. Maastricht: Maastricht University Medical Centre and the mental health institutions: GGZ Eindhoven en De Kempen, GGZ Breburg, GGZ Oost-Brabant, Vincent van Gogh voor Geestelijke Gezondheid, Mondriaan, Virenze riagg, Zuyderland GGZ, MET ggz, Universitair Centrum Sint-Jozef Kortenberg, CAPRI University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt, OPZ Rekem. Utrecht: University Medical Centre Utrecht and the mental health institutions Altrecht, GGZ Centraal and Delta). The Santander cohort was supported by Instituto de Salud Carlos III (PI020499, PI050427, PI060507), SENY Fundació (CI 2005-0308007), Fundacion Ramón Areces and Fundacion Marqués de Valdecilla (API07/011, API10/13). We thank Valdecilla Biobank for providing the biological PAFIP samples and associated data included in this study and for its help in the technical execution of this work; we also thank IDIVAL Neuroimaging Unit for its help in the acquisition and processing of imaging PAFIP data

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

PID_21_22_077_Anexo 3. Cartel de captación de profesionales sanitarios

Objetivos generales. 1. Contribuir a la humanización en la atención sanitaria por medio de una actividad innovadora en estudiantes del Grado en Medicina. 2. Difundir los resultados de la actividad a la comunidad especializada y general. Metodología. Durante este periodo los grupos de estudiantes establecidos en la asignatura Psicología (segundo cuatrimestre del Grado en Medicina) han realizado la actividad obligatoria y grupal “Entrevista a un profesional sanitario”. Resultados. En total, 159 estudiantes (72,3% mujeres) han realizado 31 entrevistas a profesionales sanitarios experimentados, preferentemente en modalidad presencial (61,3%). Los entrevistados (51,6% mujeres) son profesionales de la medicina (93,3%) de 12 especialidades diferentes, fundamentalmente Medicina Familiar y Comunitaria y Psiquiatría (25,8% y 22,6%, respectivamente). Un 9,7% corresponden a enfermería. Se han generado 31 fichas, 31 Trabajos Dirigidos y 27 grabaciones de entrevistas en audio o video. Se han presentado dos posters de la experiencia y obtenido un reconocimiento nacional. Están en curso algunas acciones, como su evaluación, la difusión por medio de Twitter y la realización de un manual de la actividad. Conclusiones. “Entrevista a un profesional sanitario” es una actividad innovadora que contribuye a la humanización de la atención sanitaria y al contacto temprano con la actividad asistencial en estudiantes de 2º curso del Grado en Medicina. La transmisión directa de su experiencia clínica a estudiantes de primeros cursos, por parte de profesionales sanitarios experimentados de diversas disciplinas y contextos, constituye un recurso valioso en Medicina y otras titulaciones de ciencias de la salud.Departamento de Pediatría e Inmunología, Obstetricia y Ginecología, Nutrición y Bromatología, Psiquiatría e Historia de la Cienci