Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.</p

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Health care resources for stroke patients in Spain, 2010: Analysis of a national survey by the Cerebrovascular Diseases Study Group

Introduction: Stroke is currently a major social health problem. For this reason, the Spanish Ministry of Health approved the Stroke National Strategy (SNS) in 2008 to improve the prevention, treatment and rehabilitation of stroke patients. This plan intends to guarantee 24-h, 365-days neurological assistance in the whole country by the end of 2010. Our aim was to analyze the situation of stroke assistance in Spain in 2009. Material and methods: A committee of neurologists practicing in the different autonomous communities (AC), and who had not participated in the preparation of the SNS, was created. A national survey was performed including the number of stroke units (SU) and their characteristics (monitoring, 24-h/7-day on-call neurology service, nursing staff ratio and the use of protocols), bed ratio of SU/100,000 people, availability of intravenous thrombolysis therapy, neurovascular intervention (NI) and telemedicine. Results: We included data from 145 hospitals. There are 39 SUs in Spain, unevenly distributed. The ratio between SU bed/number of people/AC varied from 1/75,000 to 1/1,037,000 inhabitants; Navarra and Cantabria met the goal. Intravenous thrombolysis therapy is used in 80 hospitals; the number of treatments per AC was between 7 and 536 in 2008. NI was performed in 63% of the AC, with a total of 28 qualified hospitals (although only 1 hospital performed it 24 h, 7 days a week in 2009). There were 3 hospitals offering clinical telemedicine services. Conclusions: Assistance for stroke patients has improved in Spain compared to previous years, but there are still some important differences between the AC that must be eliminated to achieve the objectives of the SNS. Resumen: Introducción: El ictus constituye un importante problema sociosanitario. Por ese motivo, el Ministerio de Sanidad aprobó en 2008 la Estrategia Nacional en Ictus (ENI) con el objetivo de mejorar la prevención, tratamiento y rehabilitación del paciente con ictus. Se pretende garantizar una atención neurológica en todo el país y a cualquier hora del día para final del 2010. Nuestro objetivo fue analizar la situación de la atención al ictus en España en el año 2009. Material y métodos: Se constituyó un comité de neurólogos de las diferentes CC. AA. que no hubieran participado en la ENI. Se elaboró una encuesta nacional que recogió el número de unidades de ictus (UI) y la dotación (monitorización, guardia de neurología 24 h/7 días, ratio de enfermería y existencia de protocolos), ratio cama UI/100.000 habitantes, presencia de trombólisis iv, intervencionismo neurovascular (INV) y telemedicina. Resultados: Se incluyeron datos de 145 hospitales. Existen 39 UI distribuidas de un modo desigual. La relación cama de UI/número de habitantes/comunidad autónoma osciló entre 1/75.000 a 1/1.037.000 habitantes, cumpliendo el objetivo Navarra y Cantabria. Se realiza trombólisis iv en 80 hospitales, el número osciló entre 7-536 tratamientos/CC. AA. durante el año 2008. Se realiza INV en el 63% de las CC. AA., teniendo 28 centros capacitados, aunque sólo 1 la realizaba en 2009 las 24 h/7 día. Existen 3 centros con telemedicina. Conclusiones: La asistencia al ictus ha mejorado en España respecto a unos años atrás, pero todavía existen importantes desigualdades por CC. AA. que deberían superarse si se quiere cumplir el objetivo de la ENI. Keywords: Stroke, Stroke thrombolysis, Stroke unit, Facilities survey, Palabras clave: Ictus, Unidades de ictus, Trombólisis, Encuesta recurso

Recursos asistenciales en ictus en España 2010: análisis de una encuesta nacional del Grupo de Estudio de Enfermedades Cerebrovasculares

Resumen: Introducción: El ictus constituye un importante problema sociosanitario. Por ese motivo, el Ministerio de Sanidad aprobó en 2008 la Estrategia Nacional en Ictus (ENI) con el objetivo de mejorar la prevención, tratamiento y rehabilitación del paciente con ictus. Se pretende garantizar una atención neurológica en todo el país y a cualquier hora del día para final del 2010. Nuestro objetivo fue analizar la situación de la atención al ictus en España en el año 2009. Material y métodos: Se constituyó un comité de neurólogos de las diferentes CC. AA. que no hubieran participado en la ENI. Se elaboró una encuesta nacional que recogió el número de unidades de ictus (UI) y la dotación (monitorización, guardia de neurología 24 h/7 días, ratio de enfermería y existencia de protocolos), ratio cama UI/100.000 habitantes, presencia de trombólisis iv, intervencionismo neurovascular (INV) y telemedicina. Resultados: Se incluyeron datos de 145 hospitales. Existen 39 UI distribuidas de un modo desigual. La relación cama de UI/número de habitantes/comunidad autónoma osciló entre 1/75.000 a 1/1.037.000 habitantes, cumpliendo el objetivo Navarra y Cantabria. Se realiza trombólisis iv en 80 hospitales, el número osciló entre 7-536 tratamientos/CC. AA. durante el año 2008. Se realiza INV en el 63% de las CC. AA., teniendo 28 centros capacitados, aunque sólo 1 la realizaba en 2009 las 24 h/7 día. Existen 3 centros con telemedicina. Conclusiones: La asistencia al ictus ha mejorado en España respecto a unos años atrás, pero todavía existen importantes desigualdades por CC. AA. que deberían superarse si se quiere cumplir el objetivo de la ENI. Abstract: Introduction: Stroke is currently a major social health problem. For this reason, the Spanish Ministry of Health approved the Stroke National Strategy (SNS) in 2008 to improve the prevention, treatment and rehabilitation of stroke patients. This plan intends to guarantee 24-hour, 365-days neurological assistance in the whole country by the end of 2010. Our aim was to analyse the situation of stroke assistance in Spain in 2009. Material and methods: A committee of neurologists practicing in the different autonomous communities (AC), and who had not participated in the preparation of the SNS, was created. A national survey was performed including the number of stroke units (SU) and their characteristics (monitoring, 24-h/7-day on-call neurology service, nursing staff ratio and the use of protocols), bed ratio of SU/100,000 people, availability of intravenous thrombolysis therapy, neurovascular intervention (NI) and telemedicine. Results: We included data from 145 hospitals. There are 39 SU in Spain, unevenly distributed. The ratio between SU bed/number of people/AC varied from 1/75,000 to 1/1,037,000 inhabitants; Navarra and Cantabria met the goal. Intravenous thrombolysis therapy is used in 80 hospitals; the number of treatments per AC was between 7 and 536 in 2008. NI was performed in the 63% of the AC, with a total of 28 qualified hospitals (although only 1 hospital performed it 24 h, 7 days a week in 2009). There were 3 hospitals offering clinical telemedicine services. Conclusions: Assistance for stroke patients has improved in Spain compared to previous years, but there are still some important differences between the AC that must be eliminated to achieve the objectives of the SNS. Palabras clave: Ictus, Unidades de ictus, Trombólisis, Encuesta recursos, Keywords: Stroke, Stroke thrombolysis, Stroke unit, Facilities surve

Analysis of stroke care resources in Spain in 2012: Have we benefitted from the Spanish Health System's stroke care strategy?

Introduction: The Spanish Health System's stroke care strategy (EISNS) is a consensus statement that was drawn up by various government bodies and scientific societies with the aim of improving quality throughout the care process and ensuring equality among regions. Our objective is to analyse existing healthcare resources and establish whether they have met EISNS targets. Material and methods: The survey on available resources was conducted by a committee of neurologists representing each of Spain's regions; the same committee also conducted the survey of 2008. The items included were the number of stroke units (SU), their resources (monitoring, neurologists on call 24 hours/7 days, nurse ratio, protocols), SU bed ratio/100 000 inhabitants, diagnostic resources (cardiac and cerebral arterial ultrasound, advanced neuroimaging), performing intravenous thrombolysis, neurovascular interventional radiology (neuro VIR), surgery for malignant middle cerebral artery (MCA) infarctions and telemedicine availability. Results: We included data from 136 hospitals and found 45 Stroke Units distributed unequally among regions. The ratio of SU beds to residents ranged from 1/74 000 to 1/1 037 000 inhabitants; only the regions of Cantabria and Navarre met the target. Neurologists performed 3237 intravenous thrombolysis procedures in 83 hospitals; thrombolysis procedures compared to the total of ischaemic strokes yielded percentages ranging from 0.3% to 33.7%. Hospitals without SUs showed varying levels of available resources. Neuro VIR is performed in every region except La Rioja, and VIR is only available on a 24 hours/7 days basis in 17 cities. Surgery for malignant MCA infarction is performed in 46 hospitals, and 5 have telemedicine. Conclusion: Stroke care has improved in terms of numbers of participating hospitals, the increased use of intravenous thrombolysis and endovascular procedures, and surgery for malignant MCA infarction. Implementation of SUs and telemedicine remain insufficient. The availability of diagnostic resources is good in most SUs and irregular in other hospitals. Regional governments should strive to ensure better care and territorial equality, which would achieve the EISNS objectives. Resumen: Introducción: La Estrategia del Ictus del Sistema Nacional de Salud (EISNS) fue un documento de consenso entre las distintas administraciones y sociedades científicas que se desarrolló con el objetivo de mejorar la calidad del proceso asistencial y garantizar la equidad territorial. Nuestro objetivo fue analizar los recursos asistenciales existentes y si se había cumplido el objetivo de la EISNS. Material y métodos: La encuesta sobre los recursos disponibles se realizó por un comité de neurólogos de cada una de las comunidades autónomas (CC.AA), los cuales también realizaron la encuesta de 2008. Los ítems incluidos fueron el número de Unidades de Ictus (UI), su dotación (monitorización, neurólogo 24 h/7 días, ratio enfermería, protocolos), ratio cama UI/100.000 habitantes, recursos diagnósticos (ecografía cardíaca y arterial cerebral, neuroimagen avanzada), realización de trombolisis intravenosa, intervencionismo neurovascular (INV), cirugía del infarto maligno de la arteria cerebral media (ACM) y disponibilidad de la telemedicina. Resultados: Se incluyeron datos de 136 hospitales. Existen 45 UI distribuidas de un modo desigual. La relación cama de UI por habitantes y comunidad autónoma osciló entre 1/74.000 a 1/1.037.000 habitantes, cumpliendo el objetivo solo Cantabria y Navarra. Se realizaron por neurólogos 3.237 trombolisis intravenosas en 83 hospitales, con un porcentaje respecto del total de ictus isquémico entre el 0,3 y el 33,7%. Los hospitales sin UI tenían una disponibilidad variable de recursos. Se realiza INV en todas las CC.AA salvo La Rioja, la disponibilidad del INV 24 h/7 días solo existe en 17 ciudades. Hay 46 centros con cirugía del infarto maligno de la ACM y 5 con telemedicina. Conclusión: La asistencia al ictus ha mejorado en cuanto al incremento de hospitales participantes, la mayor aplicación de trombolisis intravenosa y procedimientos endovasculares, también en la cirugía del infarto maligno de la ACM, pero con insuficiente implantación de UI y de la telemedicina. La disponibilidad de recursos diagnósticos es buena en la mayoría de las UI, e irregular en el resto de hospitales. Las distintas CC.AA deben avanzar para garantizar el mejor tratamiento y equidad territorial, y así conseguir el objetivo de la EISNS. Keywords: Stroke unit, Stroke treatment, Stroke facilities survey, Thrombolysis, Palabras clave: Unidad de ictus, Tratamiento ictus, Encuesta recursos, Trombolisi

Análisis de recursos asistenciales para el ictus en España en 2012: ¿beneficios de la Estrategia del Ictus del Sistema Nacional de Salud?

Resumen: Introducción: La Estrategia del Ictus del Sistema Nacional de Salud (EISNS) fue un documento de consenso entre las distintas administraciones y sociedades científicas que se desarrolló con el objetivo de mejorar la calidad del proceso asistencial y garantizar la equidad territorial. Nuestro objetivo fue analizar los recursos asistenciales existentes y si se había cumplido el objetivo de la EISNS. Material y métodos: La encuesta sobre los recursos disponibles se realizó por un comité de neurólogos de cada una de las comunidades autónomas (CC.AA), los cuales también realizaron la encuesta de 2008. Los ítems incluidos fueron el número de Unidades de Ictus (UI), su dotación (monitorización, neurólogo 24 h/7 días, ratio enfermería, protocolos), ratio cama UI/100.000 habitantes, recursos diagnósticos (ecografía cardíaca y arterial cerebral, neuroimagen avanzada), realización de trombolisis intravenosa, intervencionismo neurovascular (INV), cirugía del infarto maligno de la arteria cerebral media (ACM) y disponibilidad de la telemedicina. Resultados: Se incluyeron datos de 136 hospitales. Existen 45 UI distribuidas de un modo desigual. La relación cama de UI por habitantes y comunidad autónoma osciló entre 1/74.000 a 1/1.037.000 habitantes, cumpliendo el objetivo solo Cantabria y Navarra. Se realizaron por neurólogos 3.237 trombolisis intravenosas en 83 hospitales, con un porcentaje respecto del total de ictus isquémico entre el 0,3 y el 33,7%. Los hospitales sin UI tenían una disponibilidad variable de recursos. Se realiza INV en todas las CC.AA salvo La Rioja, la disponibilidad del INV 24 h/7 días solo existe en 17 ciudades. Hay 46 centros con cirugía del infarto maligno de la ACM y 5 con telemedicina. Conclusión: La asistencia al ictus ha mejorado en cuanto al incremento de hospitales participantes, la mayor aplicación de trombolisis intravenosa y procedimientos endovasculares, también en la cirugía del infarto maligno de la ACM, pero con insuficiente implantación de UI y de la telemedicina. La disponibilidad de recursos diagnósticos es buena en la mayoría de las UI, e irregular en el resto de hospitales. Las distintas CC.AA deben avanzar para garantizar el mejor tratamiento y equidad territorial, y así conseguir el objetivo de la EISNS. Abstract: Introduction: The Spanish Health System's stroke care strategy (EISNS) is a consensus statement that was drawn up by various government bodies and scientific societies with the aim of improving quality throughout the care process and ensuring equality among regions. Our objective is to analyse existing healthcare resources and establish whether they have met EISNS targets. Material and methods: The survey on available resources was conducted by a committee of neurologists representing each of Spain's regions; the same committee also conducted the survey of 2008. The items included were the number of stroke units (SU), their resources (monitoring, neurologists on call 24 h/7d, nurse ratio, protocols), SU bed ratio/100 000 inhabitants, diagnostic resources (cardiac and cerebral arterial ultrasound, advanced neuroimaging), performing iv thrombolysis, neurovascular interventional radiology (neuro VIR), surgery for malignant middle cerebral artery (MCA) infarctions and telemedicine availability. Results: We included data from 136 hospitals and found 45 Stroke Units distributed unequally among regions. The ratio of SU beds to residents ranged from 1/74,000 to 1/1,037,000 inhabitants; only the regions of Cantabria and Navarre met the target. Neurologists performed 3,237 intravenous thrombolysis procedures in 83 hospitals; thrombolysis procedures compared to the total of ischaemic strokes yielded percentages ranging from 0.3 to 33.7%. Hospitals without SUs showed varying levels of available resources. Neuro VIR is performed in every region except La Rioja, and VIR is only available on a 24 h/7 d basis in 17 cities. Surgery for malignant MCA infarction is performed in 46 hospitals, and 5 have telemedicine. Conclusion: Stroke care has improved in terms of numbers of participating hospitals, the increased use of intravenous thrombolysis and endovascular procedures, and surgery for malignant MCA infarction. Implementation of SUs and telemedicine remain insufficient. The availability of diagnostic resources is good in most SUs and irregular in other hospitals. Regional governments should strive to ensure better care and territorial equality, which would achieve the EISNS objectives. Palabras clave: Unidad de ictus, Tratamiento ictus, Encuesta recursos, Trombolisis, Keywords: Stroke unit, Stroke treatment, Stroke facilities survey, Thrombolysi

A MHz-repetition-rate hard X-ray free-electron laser driven by a superconducting linear accelerator

International audienceThe European XFEL is a hard X-ray free-electron laser (FEL) based on a high-electron-energy superconducting linear accelerator. The superconducting technology allows for the acceleration of many electron bunches within one radio-frequency pulse of the accelerating voltage and, in turn, for the generation of a large number of hard X-ray pulses. We report on the performance of the European XFEL accelerator with up to 5,000 electron bunches per second and demonstrating a full energy of 17.5 GeV. Feedback mechanisms enable stabilization of the electron beam delivery at the FEL undulator in space and time. The measured FEL gain curve at 9.3 keV is in good agreement with predictions for saturated FEL radiation. Hard X-ray lasing was achieved between 7 keV and 14 keV with pulse energies of up to 2.0 mJ. Using the high repetition rate, an FEL beam with 6 W average power was created

Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial

Background: Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial. Methods: NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy. Findings: Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22–1·36), and the risk was similar for those without known PFO (1·06; 0·84–1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51–8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69–4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24–0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity. Interpretation: Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted. Funding: Bayer and Janssen

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(1,2). This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories