| 1. |
- Mishra, A., et al.
(författare)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Guisado-Clavero, M., et al.
(författare)
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The role of primary health care in long-term care facilities during the COVID-19 pandemic in 30 European countries: a retrospective descriptive study (Eurodata study)
- 2023
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Ingår i: Primary Health Care Research and Development. - 1463-4236. ; 24
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Tidskriftsartikel (refereegranskat)abstract
- Background and aim:Primary health care (PHC) supported long-term care facilities (LTCFs) in attending COVID-19 patients. The aim of this study is to describe the role of PHC in LTCFs in Europe during the early phase of the pandemic.Methods:Retrospective descriptive study from 30 European countries using data from September 2020 collected with an ad hoc semi-structured questionnaire. Related variables are SARS-CoV-2 testing, contact tracing, follow-up, additional testing, and patient care.Results:Twenty-six out of the 30 European countries had PHC involvement in LTCFs during the COVID-19 pandemic. PHC participated in initial medical care in 22 countries, while, in 15, PHC was responsible for SARS-CoV-2 test along with other institutions. Supervision of individuals in isolation was carried out mostly by LTCF staff, but physical examination or symptom's follow-up was performed mainly by PHC.Conclusion:PHC has participated in COVID-19 pandemic assistance in LTCFs in coordination with LTCF staff, public health officers, and hospitals.
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| 3. |
- Ares-Blanco, S., et al.
(författare)
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Clinical pathway of COVID-19 patients in primary health care in 30 European countries: Eurodata study
- 2023
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Ingår i: European Journal of General Practice. - : Informa UK Limited. - 1381-4788 .- 1751-1402. ; 29:2
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundMost COVID-19 patients were treated in primary health care (PHC) in Europe.ObjectivesTo demonstrate the scope of PHC workflow during the COVID-19 pandemic emphasising similarities and differences of patient's clinical pathways in Europe.MethodsDescriptive, cross-sectional study with data acquired through a semi-structured questionnaire in PHC in 30 European countries, created ad hoc and agreed upon among all researchers who participated in the study. GPs from each country answered the approved questionnaire. Main variable: PHC COVID-19 acute clinical pathway. All variables were collected from each country as of September 2020.ResultsCOVID-19 clinics in PHC facilities were organised in 8/30. Case detection and testing were performed in PHC in 27/30 countries. RT-PCR and lateral flow tests were performed in PHC in 23/30, free of charge with a medical prescription. Contact tracing was performed mainly by public health authorities. Mandatory isolation ranged from 5 to 14 days. Sick leave certification was given exclusively by GPs in 21/30 countries. Patient hotels or other resources to isolate patients were available in 12/30. Follow-up to monitor the symptoms and/or new complementary tests was made mainly by phone call (27/30). Chest X-ray and phlebotomy were performed in PHC in 18/30 and 23/30 countries, respectively. Oxygen and low-molecular-weight heparin were available in PHC (21/30).ConclusionIn Europe PHC participated in many steps to diagnose, treat and monitor COVID-19 patients. Differences among countries might be addressed at European level for the management of future pandemics.
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| 4. |
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| 5. |
- Horsch, S., et al.
(författare)
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Randomized Control Trial of Postnatal rhIGF-1/rhIGFBP-3 Replacement in Preterm Infants: Post-hoc Analysis of Its Effect on Brain Injury
- 2020
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Ingår i: Frontiers in Pediatrics. - : Frontiers Media SA. - 2296-2360. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Postnatal insulin-like growth factor-1 (IGF-1) replacement with recombinant human (rh)IGF-1 and IGF binding protein-3 (rhIGF-1/rhIGFBP-3) is being studied as a potential treatment to reduce comorbidities of prematurity. We have recently reported on a phase II, multicenter, randomized, controlled trial comparing postnatal rhIGF-1/rhIGFBP-3 replacement with standard of care (SOC) in extremely preterm infants (NCT01096784). Maximum severity of retinopathy of prematurity was the primary endpoint of the trial and presence of GMH-IVH/PHI one of the pre-specified secondary endpoints. Infants therefore received serial cranial ultrasound scans (CUS) between birth and term age. In this post-hoc analysis we present a detailed analysis of the CUS data of this trial and evaluate the effect of postnatal rhIGF-1/rhIGFBP-3 replacement on the incidence of different kinds of brain injury in extremely preterm infants. Methods: This report is an exploratory post-hoc analysis of a phase II trial in which infants <28 weeks gestational age were randomly allocated to rhIGF-1/rhIGFBP-3 or SOC. Serial cranial ultrasounds were performed between birth and term-equivalent age. Presence of germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH), periventricular hemorrhagic infarction (PHI), post-hemorrhagic ventricular dilatation, and white matter injury (WMI) were scored by two independent masked readers. Results: The analysis included 117 infants; 58 received rhIGF-1/rhIGFBP-3 and 59 received SOC. A trend toward less grade II-III GMH-IVH and PHI was observed in treated infants vs. SOC. A subanalysis of infants without evidence of GMH-IVH at study entry (n = 104) showed reduced progression to GMH-IVH in treated infants (25.0% [13/52] vs. 40.4% [21/52]; not significant). No effects of rhIGF-1/rhIGFBP-3 on WMI were observed. Conclusion: The potential protective effect of rhIGF-1/rhIGFBP-3 on the occurrence of GMH-IVH/PHI appeared most pronounced in infants with no evidence of GMH-IVH at treatment start.
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| 6. |
- Kals, Mart, et al.
(författare)
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A genome-wide association study of outcome from traumatic brain injury
- 2022
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 77
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Factors such as age, pre-injury health, and injury severity, account for less than 35% of outcome variability in traumatic brain injury (TBI). While some residual outcome variability may be attributable to genetic factors, published candidate gene association studies have often been underpowered and subject to publication bias.METHODS: We performed the first genome- and transcriptome-wide association studies (GWAS, TWAS) of genetic effects on outcome in TBI. The study population consisted of 5268 patients from prospective European and US studies, who attended hospital within 24 h of TBI, and satisfied local protocols for computed tomography.FINDINGS: The estimated heritability of TBI outcome was 0·26. GWAS revealed no genetic variants with genome-wide significance (p < 5 × 10-8), but identified 83 variants in 13 independent loci which met a lower pre-specified sub-genomic statistical threshold (p < 10-5). Similarly, none of the genes tested in TWAS met tissue-wide significance. An exploratory analysis of 75 published candidate variants associated with 28 genes revealed one replicable variant (rs1800450 in the MBL2 gene) which retained significance after correction for multiple comparison (p = 5·24 × 10-4).INTERPRETATION: While multiple novel loci reached less stringent thresholds, none achieved genome-wide significance. The overall heritability estimate, however, is consistent with the hypothesis that common genetic variation substantially contributes to inter-individual variability in TBI outcome. The meta-analytic approach to the GWAS and the availability of summary data allows for a continuous extension with additional cohorts as data becomes available.FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.
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| 7. |
- Mereaux, JL, et al.
(författare)
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Increasing involvement of CAPN1 variants in spastic ataxias and phenotype-genotype correlations
- 2021
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Ingår i: Neurogenetics. - : Springer Science and Business Media LLC. - 1364-6753 .- 1364-6745. ; 22:1, s. 71-79
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Tidskriftsartikel (refereegranskat)abstract
- Spastic ataxias are rare neurogenetic disorders involving spinocerebellar and pyramidal tracts. Many genes are involved. Among them, CAPN1, when mutated, is responsible for a complex inherited form of spastic paraplegia (SPG76). We report the largest published series of 21 novel patients with nine new CAPN1 disease-causing variants and their clinical characteristics from two European university hospitals (Paris and Stockholm). After a formal clinical examination, causative variants were identified by next-generation sequencing and confirmed by Sanger sequencing. CAPN1 variants are a rare cause (~ 1.4%) of young-adult-onset spastic ataxia; however, together with all published cases, they allowed us to better describe the clinical and genetic spectra of this form. Truncating variants are the most frequent, and missense variants lead to earlier age at onset in favor of an additional deleterious effect. Cerebellar ataxia with cerebellar atrophy, dysarthria and lower limb weakness are often associated with spasticity. We also suggest that cognitive impairment and depression should be assessed specifically in the follow-up of SPG76 cases.
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| 8. |
- Tenorio, Emanuel R, et al.
(författare)
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Multicenter global early feasibility study to evaluate total endovascular arch repair using three-vessel inner branch stent-grafts for aneurysms and dissections
- 2021
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Ingår i: Journal of Vascular Surgery. - : Elsevier BV. - 1097-6809 .- 0741-5214. ; 74:4, s. 4-1065
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To evaluate the outcomes of total endovascular aortic arch repair using three-vessel inner branch stent-grafts for aneurysms and chronic dissections.METHODS: We reviewed the clinical data and outcomes of consecutive patients treated by total endovascular aortic arch repair at eight academic centers using three-vessel inner branch stent-grafts (William Cook Europe, Bjaeverskov, Denmark) between 2016 to 2019. All patients received three vessel designs with two antegrade and one retrograde inner branch, which was used to incorporate the innominate (IA), left common carotid (LCCA) and left subclavian arteries (LSA). The antegrade inner branches were accessed via carotid or upper extremity access. A preloaded catheter was used for access to the retrograde LSA branch via trans-femoral approach. End-points were technical success, mortality, major adverse events (MAEs), any stroke (minor or major) or transient ischemia attack (TIA), secondary interventions, target vessel patency, target vessel instability, aneurysm-related mortality and patient survival.RESULTS: There were 39 patients (31 male patients [79%], mean age 70±7) treated for 14 (36%) degenerative and 25 (64%) chronic post-dissection arch aneurysms. Clinical characteristics included American Society of Anesthesiologist (ASA) classification > 3 in 28 patients (95%) and prior median sternotomy for ascending aortic repair in 28 patients (72%). Technical success rate was 100%. There were two in-hospital or 30-day deaths (5%) and two strokes (one minor). Combined mortality/any stroke rate was 8% (n=3). MAEs occurred in 10 patients (26%), including respiratory failure in four patients (10%) and estimated blood loss >1L, myocardial infarction and acute kidney injury in two patients each (5%). Median follow up was 3.2 months (IQR, 1 to 14). Twelve patients (31%) required secondary interventions to treat vascular access complications in five patients, endoleak in six patients (three type II, one type IC, one type IA/IB, one type IIIA) and target vessel stenosis in one patient. At 1-year, primary and secondary patency rates and freedom from target vessel instability were 95%±5%, 100% and 91%±5%. Freedom from aortic-related mortality and patient survival were 94%±4% and 90%±6%, respectively.CONCLUSION: This multicenter global experience demonstrates the technical feasibility and safety of total endovascular aortic arch repair for aneurysms and chronic dissections using three-vessel inner branch stent-grafts. Mortality and stroke rates compare favorably to open surgical repair in a higher risk group of patients. Rate of secondary interventions was high (31%), emphasizing need for larger experience and longer follow-up.
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