Tratamiento de reperfusión en el ictus isquémico agudo por disección arterial cervicocerebral: descripción de los resultados de un estudio nacional multicéntrico

Introducción El ictus isquémico (II) por disección arterial cervicocerebral (DAC) es una entidad infrecuente y existen pocos datos sobre el uso de terapias de reperfusión como la fibrinólisis intravenosa y la trombectomía mecánica. Se analizó el uso de dichas terapias en pacientes con II por DAC y se comparó con aquellos pacientes reperfundidos con II por otras causas. Método Estudio observacional retrospectivo multicéntrico de pacientes con II por DAC basado en el Registro Nacional de Ictus de la Sociedad Española de Neurología durante el periodo 2011-2019. Se realizaron análisis comparativos entre: a) pacientes con DAC tratados y no tratados con terapias de reperfusión y b) pacientes reperfundidos con II por DAC y pacientes reperfundidos con II por otras causas. Se incluyeron variables epidemiológicas, del ictus y resultados al alta y a los 3 meses. Resultados Un total de 21.037 pacientes con II fueron incluidos; 223 (1%) fueron por DAC y 68 (30%) recibieron tratamiento de reperfusión. El uso de tratamientos de reperfusión fue menor en los casos de DAC de arteria vertebral y mayor en los casos de oclusión carotídea. Los pacientes con II por DAC reperfundidos respecto a aquellos con II reperfundidos por otras causas fueron más jóvenes, la trombectomía mecánica se utilizó más y la fibrinólisis intravenosa menos. Las complicaciones hemorrágicas, la mortalidad y la autonomía a los 3 meses fueron similares. Conclusiones Las terapias de reperfusión se usan con frecuencia en los pacientes con II por DAC. Los resultados demuestran eficacia y seguridad y son equiparables a los pacientes tratados con terapias de reperfusión por II de otras causas. Introduction Ischaemic stroke (IS) due to cervical and cerebral artery dissection (CAD) is a rare entity, and few data are available on the use of such reperfusion therapies as intravenous fibrinolysis and mechanical thrombectomy in these patients. We analysed the use of these treatments in patients with IS due to CAD and compared them against patients receiving reperfusion treatment for IS of other aetiologies. Method We conducted an observational, retrospective, multicentre study of patients with IS due to CAD recorded in the National Stroke Registry of the Spanish Society of Neurology during the period 2011-2019. Comparative analyses were performed between: a) patients with CAD treated and not treated with reperfusion therapies and b) patients treated with reperfusion for IS due to CAD and patients treated with reperfusion for IS due to other causes. Epidemiological data, stroke variables, and outcomes at discharge and at 3 months were included in the analysis. Results The study included 21, 037 patients with IS: 223 (1%) had IS due to CAD, of whom 68 (30%) received reperfusion treatment. Reperfusion treatments were used less frequently in cases of vertebral artery dissection and more frequently in patients with carotid artery occlusion. Compared to patients with IS due to other causes, patients with CAD were younger, more frequently underwent mechanical thrombectomy, and less frequently received intravenous fibrinolysis. Rates of haemorrhagic complications, mortality, and independence at 3 months were similar in both groups. Conclusions Reperfusion therapy is frequently used in patients with IS due to CAD. The outcomes of these patients demonstrate the efficacy and safety of reperfusion treatments, and are comparable to the outcomes of patients with IS due to other aetiologies

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Reperfusion treatment in acute ischaemic stroke due to cervical and cerebral artery dissection: results of a Spanish national multicentre study

Introducción: El ictus isquémico (II) por disección arterial cervicocerebral (DAC) es una entidad infrecuente y existen pocos datos sobre el uso de terapias de reperfusión como la fibrinólisis intravenosa y la trombectomía mecánica. Se analizó el uso de dichas terapias en pacientes con II por DAC y se comparó con aquellos pacientes reperfundidos con II por otras causas. Método: Estudio observacional retrospectivo multicéntrico de pacientes con II por DAC basado en el Registro Nacional de Ictus de la Sociedad Española de Neurología durante el periodo 2011-2019. Se realizaron análisis comparativos entre: a) pacientes con DAC tratados y no tratados con terapias de reperfusión y b) pacientes reperfundidos con II por DAC y pacientes reperfundidos con II por otras causas. Se incluyeron variables epidemiológicas, del ictus y resultados al alta y a los 3 meses. Resultados: Un total de 21.037 pacientes con II fueron incluidos; 223 (1%) fueron por DAC y 68 (30%) recibieron tratamiento de reperfusión. El uso de tratamientos de reperfusión fue menor en los casos de DAC de arteria vertebral y mayor en los casos de oclusión carotídea. Los pacientes con II por DAC reperfundidos respecto a aquellos con II reperfundidos por otras causas fueron más jóvenes, la trombectomía mecánica se utilizó más y la fibrinólisis intravenosa menos. Las complicaciones hemorrágicas, la mortalidad y la autonomía a los 3 meses fueron similares. Conclusiones: Las terapias de reperfusión se usan con frecuencia en los pacientes con II por DAC. Los resultados demuestran eficacia y seguridad y son equiparables a los pacientes tratados con terapias de reperfusión por II de otras causas.Introduction: Ischaemic stroke (IS) due to cervical and cerebral artery dissection (CAD) is a rare entity, and few data are available on the use of such reperfusion therapies as intravenous fibrinolysis and mechanical thrombectomy in these patients. We analysed the use of these treatments in patients with IS due to CAD and compared them against patients receiving reperfusion treatment for IS of other aetiologies. Method: We conducted an observational, retrospective, multicentre study of patients with IS due to CAD recorded in the National Stroke Registry of the Spanish Society of Neurology during the period 2011-2019. Comparative analyses were performed between: a) patients with CAD treated and not treated with reperfusion therapies and b) patients treated with reperfusion for IS due to CAD and patients treated with reperfusion for IS due to other causes. Epidemiological data, stroke variables, and outcomes at discharge and at 3 months were included in the analysis. Results: The study included 21,037 patients with IS: 223 (1%) had IS due to CAD, of whom 68 (30%) received reperfusion treatment. Reperfusion treatments were used less frequently in cases of vertebral artery dissection and more frequently in patients with carotid artery occlusion. Compared to patients with IS due to other causes, patients with CAD were younger, more frequently underwent mechanicalthrombectomy, and less frequently received intravenous fibri nolysis. Rates of haemorrhagic complications, mortality, and independence at 3 months were similar in both groups. Conclusions: Reperfusion therapy is frequently used in patients with IS due to CAD. The outcomes of these patients demonstrate the efficacy and safety of reperfusion treatments, and are comparable to the outcomes of patients with IS due to other aetiologie

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Frontal fibrosing alopecia shows robust T helper 1 and Janus kinase 3 skewing

Frontal fibrosing alopecia (FFA) is a scarring alopecia with unclear pathogenesis and a progressive course. The disease has a major impact on patients' quality of life and there is a lack of effective treatment to halt disease progression. We profiled lesional and nonlesional scalp biopsies collected in 2017 from patients with FFA (n = 12) compared with scalp biopsies from patients with alopecia areata (AA) (n = 8) and controls (n = 8) to evaluate gene and protein expression, including the primary outcome (CXCL9). We determined significant differences between biomarkers using a two-sided Student's t-test adjusting P-values by false discovery rate. Significant increases were seen in CD8+ cytotoxic T cells, CD11c+ dendritic cells, CD103+ and CD69+ tissue-resident memory T cells in FFA and AA vs. control scalp (P < 0·05), with corresponding significantly upregulated granzyme B mRNA, particularly in FFA (P < 0·01). In AA, cellular infiltrates were primarily concentrated at the bulb, while in FFA these were mainly localized at the bulge. FFA demonstrated significant upregulation of T helper 1/intereferon (IFN) (IFN-γ, CXCL9/CXCL10), the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway (STAT1, JAK3) and fibrosis-related products (vimentin, fibronectin; P < 0·05), with no concomitant downregulation of hair keratins and the T-regulatory marker, forkhead box P3, which were decreased in AA. The stem cell markers CD200 and K15 demonstrated significantly reduced expression only in FFA (P < 0·05). These data suggest that follicular damage and loss of stem cells in FFA may be mediated through immune attack in the bulge region, with secondary fibrosis and reduced but still detectable stem cells. JAK/STAT-targeting treatments may be able to prevent permanent follicular destruction and fibrosis in early disease stages

Tratamiento de reperfusión en el ictus isquémico agudo por disección arterial cervicocerebral: descripción de los resultados de un estudio nacional multicéntrico

Resumen: Introducción: El ictus isquémico (II) por disección arterial cervicocerebral (DAC) es una entidad infrecuente y existen pocos datos sobre el uso de terapias de reperfusión como la fibrinólisis intravenosa y la trombectomía mecánica. Se analizó el uso de dichas terapias en pacientes con II por DAC y se comparó con aquellos pacientes reperfundidos con II por otras causas. Método: Estudio observacional retrospectivo multicéntrico de pacientes con II por DAC basado en el Registro Nacional de Ictus de la Sociedad Española de Neurología durante el periodo 2011-2019. Se realizaron análisis comparativos entre: a) pacientes con DAC tratados y no tratados con terapias de reperfusión y b) pacientes reperfundidos con II por DAC y pacientes reperfundidos con II por otras causas. Se incluyeron variables epidemiológicas, del ictus y resultados al alta y a los 3 meses. Resultados: Un total de 21.037 pacientes con II fueron incluidos; 223 (1%) fueron por DAC y 68 (30%) recibieron tratamiento de reperfusión. El uso de tratamientos de reperfusión fue menor en los casos de DAC de arteria vertebral y mayor en los casos de oclusión carotídea. Los pacientes con II por DAC reperfundidos respecto a aquellos con II reperfundidos por otras causas fueron más jóvenes, la trombectomía mecánica se utilizó más y la fibrinólisis intravenosa menos. Las complicaciones hemorrágicas, la mortalidad y la autonomía a los 3 meses fueron similares. Conclusiones: Las terapias de reperfusión se usan con frecuencia en los pacientes con II por DAC. Los resultados demuestran eficacia y seguridad y son equiparables a los pacientes tratados con terapias de reperfusión por II de otras causas. Abstract: Introduction: Ischaemic stroke (IS) due to cervical and cerebral artery dissection (CAD) is a rare entity, and few data are available on the use of such reperfusion therapies as intravenous fibrinolysis and mechanical thrombectomy in these patients. We analysed the use of these treatments in patients with IS due to CAD and compared them against patients receiving reperfusion treatment for IS of other aetiologies. Method: We conducted an observational, retrospective, multicentre study of patients with IS due to CAD recorded in the National Stroke Registry of the Spanish Society of Neurology during the period 2011-2019. Comparative analyses were performed between: a) patients with CAD treated and not treated with reperfusion therapies and b) patients treated with reperfusion for IS due to CAD and patients treated with reperfusion for IS due to other causes. Epidemiological data, stroke variables, and outcomes at discharge and at 3 months were included in the analysis. Results: The study included 21,037 patients with IS: 223 (1%) had IS due to CAD, of whom 68 (30%) received reperfusion treatment. Reperfusion treatments were used less frequently in cases of vertebral artery dissection and more frequently in patients with carotid artery occlusion. Compared to patients with IS due to other causes, patients with CAD were younger, more frequently underwent mechanical thrombectomy, and less frequently received intravenous fibrinolysis. Rates of haemorrhagic complications, mortality, and independence at 3 months were similar in both groups. Conclusions: Reperfusion therapy is frequently used in patients with IS due to CAD. The outcomes of these patients demonstrate the efficacy and safety of reperfusion treatments, and are comparable to the outcomes of patients with IS due to other aetiologies