| 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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| 4. |
- Weinstein, John N., et al.
(författare)
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The cancer genome atlas pan-cancer analysis project
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:10, s. 1113-1120
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Forskningsöversikt (refereegranskat)abstract
- The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. © 2013 Nature America, Inc. All rights reserved.
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| 8. |
- Madireddy, L, et al.
(författare)
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A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2236-
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified more than 50,000 unique associations with common human traits. While this represents a substantial step forward, establishing the biology underlying these associations has proven extremely difficult. Even determining which cell types and which particular gene(s) are relevant continues to be a challenge. Here, we conduct a cell-specific pathway analysis of the latest GWAS in multiple sclerosis (MS), which had analyzed a total of 47,351 cases and 68,284 healthy controls and found more than 200 non-MHC genome-wide associations. Our analysis identifies pan immune cell as well as cell-specific susceptibility genes in T cells, B cells and monocytes. Finally, genotype-level data from 2,370 patients and 412 controls is used to compute intra-individual and cell-specific susceptibility pathways that offer a biological interpretation of the individual genetic risk to MS. This approach could be adopted in any other complex trait for which genome-wide data is available.
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| 12. |
- Lovestone, S., et al.
(författare)
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The European medical information framework: A novel ecosystem for sharing healthcare data across Europe
- 2020
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Ingår i: Learning Health Systems. - : Wiley. - 2379-6146. ; 4:2
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Tidskriftsartikel (refereegranskat)abstract
- Introduction The European medical information framework (EMIF) was an Innovative Medicines Initiative project jointly supported by the European Union and the European Federation of Pharmaceutical Industries and Associations, that generated a common technology and governance framework to identify, assess and (re)use healthcare data, to facilitate real-world data research. The objectives of EMIF included providing a unified platform to support a wide range of studies within two verification programmes-Alzheimer's disease (EMIF-AD), and metabolic consequences of obesity (EMIF-MET). Methods The EMIF platform was built around two main data-types: electronic health record data and research cohort data, and the platform architecture composed of a set of tools designed to enable data discovery and characterisation. This included the EMIF catalogue, which allowed users to find relevant data sources, including the data-types collected. Data harmonisation via a common data model were central to the project especially for population data sources. EMIF also developed an ethical code of practice to ensure data protection, patient confidentiality and compliance with the European Data Protection Directive, and GDPR. Results Currently 18 population-based disease agnostic and 60 cohort-based Alzheimer's data partners from across 14 countries are contained within the catalogue, and this will continue to expand. The work conducted in EMIF-AD and EMIF-MET includes standardizing cohorts, summarising baseline characteristics of patients, developing diagnostic algorithms, epidemiological studies, identifying and validating novel biomarkers and selecting potential patient samples for pharmacological intervention. Conclusions EMIF was designed to provide a sustainable model as demonstrated by the sustainability plans for EMIF-AD. Although network-wide studies using EMIF were not conducted during this project to evaluate its sustainability, learning from EMIF will be used in the follow-on IMI-2 project, European Health Data and Evidence Network (EHDEN). Furthermore, EMIF has facilitated collaborations between partners and continues to promote a wider adoption of principles, technology and architecture through some of its continued work.
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| 13. |
- Rahaghi, FF, et al.
(författare)
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Delphi consensus recommendations for a treatment algorithm in pulmonary sarcoidosis
- 2020
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Ingår i: European respiratory review : an official journal of the European Respiratory Society. - : European Respiratory Society (ERS). - 1600-0617. ; 29:155
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Tidskriftsartikel (refereegranskat)abstract
- Pulmonary sarcoidosis presents substantial management challenges, with limited evidence on effective therapies and phenotypes. In the absence of definitive evidence, expert consensus can supply clinically useful guidance in medicine. An international panel of 26 experts participated in a Delphi process to identify consensus on pharmacological management in sarcoidosis with the development of preliminary recommendations.The modified Delphi process used three rounds. The first round focused on qualitative data collection with open-ended questions to ensure comprehensive inclusion of expert concepts. Rounds 2 and 3 applied quantitative assessments using an 11-point Likert scale to identify consensus.Key consensus points included glucocorticoids as initial therapy for most patients, with non-biologics (immunomodulators), usually methotrexate, considered in severe or extrapulmonary disease requiring prolonged treatment, or as a steroid-sparing intervention in cases with high risk of steroid toxicity. Biologic therapies might be considered as additive therapy if non-biologics are insufficiently effective or are not tolerated with initial biologic therapy, usually with a tumour necrosis factor-α inhibitor, typically infliximab.The Delphi methodology provided a platform to gain potentially valuable insight and interim guidance while awaiting evidenced-based contributions.
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- El-Khateeb, Eman, et al.
(författare)
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Using Prior Knowledge on Systems Through PBPK to Gain Further Insight into Routine Clinical Data on Trough Concentrations: The Case of Tacrolimus in Chronic Kidney Disease
- 2023
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Ingår i: Therapeutic Drug Monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356 .- 1536-3694. ; 45:6, s. 743-753
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Tidskriftsartikel (refereegranskat)abstract
- Background: Routine therapeutic drug monitoring (TDM) relies heavily on measuring trough drug concentrations. Trough concentrations are affected not only by drug bioavailability and clearance, but also by various patient and disease factors and the volume of distribution. This often makes interpreting differences in drug exposure from trough data challenging. This study aimed to combine the advantages of top-down analysis of therapeutic drug monitoring data with bottom-up physiologically-based pharmacokinetic (PBPK) modeling to investigate the effect of declining renal function in chronic kidney disease (CKD) on the nonrenal intrinsic metabolic clearance (CLint) of tacrolimus as a case example.Methods: Data on biochemistry, demographics, and kidney function, along with 1167 tacrolimus trough concentrations for 40 renal transplant patients, were collected from the Salford Royal Hospital's database. A reduced PBPK model was developed to estimate CLint for each patient. Personalized unbound fractions, blood-to-plasma ratios, and drug affinities for various tissues were used as priors to estimate the apparent volume of distribution. Kidney function based on the estimated glomerular filtration rate (eGFR) was assessed as a covariate for CLint using the stochastic approximation of expectation and maximization method.Results: At baseline, the median (interquartile range) eGFR was 45 (34.5-55.5) mL/min/1.73 m2. A significant but weak correlation was observed between tacrolimus CLint and eGFR (r = 0.2, P < 0.001). The CLint declined gradually (up to 36%) with CKD progression. Tacrolimus CLint did not differ significantly between stable and failing transplant patients.Conclusions: Kidney function deterioration in CKD can affect nonrenal CLint for drugs that undergo extensive hepatic metabolism, such as tacrolimus, with critical implications in clinical practice. This study demonstrates the advantages of combining prior system information (via PBPK) to investigate covariate effects in sparse real-world datasets.
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| 18. |
- Jensterle, M, et al.
(författare)
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The Relationship between COVID-19 and Hypothalamic-Pituitary-Adrenal Axis: A Large Spectrum from Glucocorticoid Insufficiency to Excess-The CAPISCO International Expert Panel
- 2022
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Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 23:13
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Tidskriftsartikel (refereegranskat)abstract
- Coronavirus disease 2019 (COVID-19) is a highly heterogeneous disease regarding severity, vulnerability to infection due to comorbidities, and treatment approaches. The hypothalamic–pituitary–adrenal (HPA) axis has been identified as one of the most critical endocrine targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that might significantly impact outcomes after infection. Herein we review the rationale for glucocorticoid use in the setting of COVID-19 and emphasize the need to have a low index of suspicion for glucocorticoid-induced adrenal insufficiency, adjusting for the glucocorticoid formulation used, dose, treatment duration, and underlying health problems. We also address several additional mechanisms that may cause HPA axis dysfunction, including critical illness-related corticosteroid insufficiency, the direct cytopathic impacts of SARS-CoV-2 infection on the adrenals, pituitary, and hypothalamus, immune-mediated inflammations, small vessel vasculitis, microthrombotic events, the resistance of cortisol receptors, and impaired post-receptor signaling, as well as the dissociation of ACTH and cortisol regulation. We also discuss the increased risk of infection and more severe illness in COVID-19 patients with pre-existing disorders of the HPA axis, from insufficiency to excess. These insights into the complex regulation of the HPA axis reveal how well the body performs in its adaptive survival mechanism during a severe infection, such as SARS-CoV-2, and how many parameters might disbalance the outcomes of this adaptation.
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| 20. |
- Langhorne, P, et al.
(författare)
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Is stroke unit care portable? A systematic review of the clinical trials
- 2005
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Ingår i: Age and Ageing. - : Oxford University Press (OUP). - 0002-0729 .- 1468-2834. ; 34:4, s. 324-330
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Tidskriftsartikel (refereegranskat)abstract
- Background: It is not known if mobile stroke teams can achieve the good results seen in trials of geographically discrete stroke wards (stroke units). Objective: To establish the effectiveness of mobile stroke teams. Design: Systematic review of controlled clinical trials that compared peripatetic systems of organised stroke care (stroke team care) with alternative hospital services. Methods: Systematic review and meta-analysis (using Cochrane Collaboration methodology and involving the primary trialists). Clinical outcomes included death, dependency, the need for institutional care and measures of the process of care such as the delivery of key investigations and treatments. Results: Six clinical trials (1,085 patients) were identified, five (781 patients) compared some form of stroke team care with conventional care in general medical wards and one (304 patients) compared team care with a comprehensive stroke unit. Compared with care in general wards, stroke team care improved some aspects of the process of care, but clinical outcomes were similar. Compared with a comprehensive stroke unit, stroke team patients were significantly less likely to survive (P< 0.001), return home (P< 0.001) or regain independence (P< 0.0001). Most aspects of the process of care were also poorer than in the stroke unit. Conclusions: Care from a mobile stroke team had no major impact on death, dependency or the need for institutional care. © The Author 2005. Published by Oxford University Press. All rights reserved.
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| 21. |
- Langhorne, P., et al.
(författare)
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Stroke Unit Care Benefits Patients With Intracerebral Hemorrhage Systematic Review and Meta-analysis
- 2013
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Ingår i: Stroke. - : Ovid Technologies (Wolters Kluwer Health). - 0039-2499 .- 1524-4628. ; 44:11, s. 3044-3049
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose Patients with any type of stroke managed in organized inpatient (stroke unit) care are more likely to survive, return home, and regain independence. However, it is uncertain whether these benefits apply equally to patients with intracerebral hemorrhage and ischemic stroke. Methods We conducted a secondary analysis of a systematic review of controlled clinical trials comparing stroke unit care with general ward care, including only trials published after 1990 that could separately report outcomes for patients with intracerebral hemorrhage and ischemic stroke. We performed random-effects meta-analyses and tested for subgroup interactions by stroke type. Results We identified 13 trials (3570 patients) of modern stroke unit care that recruited patients with intracerebral hemorrhage and ischemic stroke, of which 8 trials provided data on 2657 patients. Stroke unit care reduced death or dependency (risk ratio [RR], 0.81; 95% confidence interval [CI], 0.471-0.92; P=0.0009; I-2=60%) with no difference in benefits for patients with intracerebral hemorrhage (RR, 0.79; 95% CI, 0.61-1.00) than patients with ischemic stroke (RR, 0.82; 95% CI, 0.70-0.97; P-interaction=0.77). Stroke unit care reduced death (RR, 0.79; 95% CI, 0.64-0.97; P=0.02; I-2=49%) to a greater extent for patients with intracerebral hemorrhage (RR, 0.73; 95% CI, 0.54-0.97) than patients with ischemic stroke (RR, 0.82; 95%, CI 0.61-1.09), but this difference was not statistically significant (P-interaction=0.58). Conclusions Patients with intracerebral hemorrhage seem to benefit at least as much as patients with ischemic stroke from organized inpatient (stroke unit) care.
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| 24. |
- Mainas, G, et al.
(författare)
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Associations between Periodontitis, COVID-19, and Cardiometabolic Complications: Molecular Mechanisms and Clinical Evidence
- 2023
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Ingår i: Metabolites. - : MDPI AG. - 2218-1989. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Periodontitis is a microbially driven, host-mediated disease that leads to loss of periodontal attachment and resorption of bone. It is associated with the elevation of systemic inflammatory markers and with the presence of systemic comorbidities. Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the majority of patients have mild symptoms, others experience important complications that can lead to death. After the spread of the COVID-19 pandemic, several investigations demonstrating the possible relationship between periodontitis and COVID-19 have been reported. In addition, both periodontal disease and COVID-19 seem to provoke and/or impair several cardiometabolic complications such as cardiovascular disease, type 2 diabetes, metabolic syndrome, dyslipidemia, insulin resistance, obesity, non-alcoholic fatty liver disease, and neurological and neuropsychiatric complications. Therefore, due to the increasing number of investigations focusing on the periodontitis-COVID-19 relationship and considering the severe complications that such an association might cause, this review aims to summarize all existing emerging evidence regarding the link between the periodontitis-COVID-19 axis and consequent cardiometabolic impairments.
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| 25. |
- Mann, Anita, et al.
(författare)
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Differences in DNA Condensation and Release by Lysine and Arginine Homopeptides Govern Their DNA Delivery Efficiencies
- 2011
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 8:5, s. 1729-1741
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Tidskriftsartikel (refereegranskat)abstract
- Designing of nanocarriers that can efficiently deliver therapeutic DNA payload and allow its smooth intracellular release for transgene expression is still a major constraint. The optimization of DNA nanocarriers requires thorough understanding of the chemical and structural characteristics of the vector-nucleic acid complexes and its correlation with the cellular entry, intracellular state and transfection efficiency. L-Lysine and L-arginine based cationic peptides alone or in conjugation with other vectors are known to be putative DNA delivery agents. Here we have used L-lysine and L-arginine homopeptides of three different lengths and probed their DNA condensation and release properties by using a multitude of biophysical techniques including fluorescence spectroscopy, gel electrophoresis and atomic force microscopy. Our results clearly showed that although both lysine and arginine based homopeptides condense DNA via electrostatic interactions, they follow different pattern of DNA condensation and release in vitro. While lysine homopeptides condense DNA to form both monomolecular and multimolecular complexes and show differential release of DNA in vitro depending on the peptide length, arginine homopeptides predominantly form multimolecular complexes and show complete DNA release for all peptide lengths. The cellular uptake of the complexes and their intracellular state (as observed through flow cytometry and fluorescence microscopy) seem to be controlled by the peptide chemistry. The difference in the transfection efficiency of lysine and arginine homopeptides has been rationalized in light of these observations.
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| 26. |
- Pourjabbar, Sarvenaz, et al.
(författare)
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Preliminary Results : prospective clinical study to assess image-based iterative reconstruction for abdominal computed tomography acquired at 2 radiation dose levels
- 2014
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Ingår i: Journal of computer assisted tomography. - : Lippincott Williams & Wilkins. - 0363-8715 .- 1532-3145. ; 38:1, s. 117-122
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:The objective of this study was to compare image quality for abdominal computed tomographic (CT) images acquired at 200 and 50 mA s and reconstructed with image-based iterative reconstruction.MATERIALS AND METHODS:In this institutional review board-approved prospective study, 22 patients (mean [SD] age, 64.3 [14.4] years; male-female ratio, 12:10) gave informed consent for acquisition of additional abdominal CT images on 64-slice multi-detector CT (MDCT) (Siemens Definition Flash). Standard-dose images were acquired at 200 quality reference mA s, whereas low-dose images were acquired at 50 mA s (all series: 120 kV; 5-mm section thickness; pitch, 0.9:1). The low-dose images were reconstructed with a nonlinear 3-dimensional iterative image reconstruction (3D-IIR) (SafeCT; MedicVision, Tirat Carmel, Israel) (4 settings, namely, A1, A2, A3, and A4) and were assessed by 3 abdominal radiologists for lesion detection, image noise, and visibility of small structures. CATPHAN 500 was scanned at the respective doses to obtain noise spectral density and modulation transfer function.RESULTS:Subjective image noise was unacceptable at 50-mA s filtered back projection and improved to average in 50-mA s A1 and minimal or no noise in 50-mA s A4. However, the visibility of small structures was similar to standard-dose filtered back projection images on 50-mA s A2. Objective image noise was reduced to 66% for the 50-mA s 3D-IIR images (9.08 [2.3]/26.75 [6.8]). The modulation transfer function curve demonstrated resolution improvement in the low-dose images with the 3D-IIR technique, whereas the noise spectral density curve confirmed noise suppression in the 50-mA s 3D-IIR images.CONCLUSIONS:Three-dimensional iterative image reconstruction helps to lower image noise without affecting the visibility of small structures at "moderate" settings. Diagnostically acceptable abdominal CT examinations can be acquired at 75% lower-radiation dose with the help of the image-based iterative reconstruction technique.
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