| 1. |
- Pennings, M., et al.
(författare)
-
KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia
- 2020
-
Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 28, s. 40-49
-
Tidskriftsartikel (refereegranskat)abstract
- Variants in the KIF1A gene can cause autosomal recessive spastic paraplegia 30, autosomal recessive hereditary sensory neuropathy, or autosomal (de novo) dominant mental retardation type 9. More recently, variants in KIF1A have also been described in a few cases with autosomal dominant spastic paraplegia. Here, we describe 20 KIF1A variants in 24 patients from a clinical exome sequencing cohort of 347 individuals with a mostly ‘pure’ spastic paraplegia. In these patients, spastic paraplegia was slowly progressive and mostly pure, but with a highly variable disease onset (0–57 years). Segregation analyses showed a de novo occurrence in seven cases, and a dominant inheritance pattern in 11 families. The motor domain of KIF1A is a hotspot for disease causing variants in autosomal dominant spastic paraplegia, similar to mental retardation type 9 and recessive spastic paraplegia type 30. However, unlike these allelic disorders, dominant spastic paraplegia was also caused by loss-of-function variants outside this domain in six families. Finally, three missense variants were outside the motor domain and need further characterization. In conclusion, KIF1A variants are a frequent cause of autosomal dominant spastic paraplegia in our cohort (6–7%). The identification of KIF1A loss-of-function variants suggests haploinsufficiency as a possible mechanism in autosomal dominant spastic paraplegia. © 2019, The Author(s).
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
- van der Wouden, C. H., et al.
(författare)
-
Implementing Pharmacogenomics in Europe : Design and Implementation Strategy of the Ubiquitous Pharmacogenomics Consortium
- 2017
-
Ingår i: Clinical Pharmacology and Therapeutics. - : WILEY. - 0009-9236 .- 1532-6535. ; 101:3, s. 341-358
-
Tidskriftsartikel (refereegranskat)abstract
- Despite scientific and clinical advances in the field of pharmacogenomics (PGx), application into routine care remains limited. Opportunely, several implementation studies and programs have been initiated over recent years. This article presents an overview of these studies and identifies current research gaps. Importantly, one such gap is the undetermined collective clinical utility of implementing a panel of PGx-markers into routine care, because the evidence base is currently limited to specific, individual drug-gene pairs. The Ubiquitous Pharmacogenomics (U-PGx) Consortium, which has been funded by the European Commission's Horizon-2020 program, aims to address this unmet need. In a prospective, block-randomized, controlled clinical study (PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions [PREPARE]), pre-emptive genotyping of a panel of clinically relevant PGx-markers, for which guidelines are available, will be implemented across healthcare institutions in seven European countries. The impact on patient outcomes and cost-effectiveness will be investigated. The program is unique in its multicenter, multigene, multidrug, multi-ethnic, and multi-healthcare system approach.
|
|
| 5. |
- Swen, JesseJ, et al.
(författare)
-
A 12-gene pharmacogenetic panel to prevent adverse drug reactions : an open-label, multicentre, controlled, cluster-randomised crossover implementation study
- 2023
-
Ingår i: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 401:10374, s. 347-356
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene-drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed.Methods: We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug-gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug-gene interaction in the study group versus the control group were compared, and only if the difference was statistically significant was an analysis done that included all of the patients in the study. Outcomes were compared between the study and control groups, both for patients with an actionable drug-gene interaction test result (ie, a result for which the DPWG recommended a change to standard-of-care drug treatment) and for all patients who received at least one dose of index drug. The safety analysis included all participants who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03093818 and is closed to new participants.Findings: Between March 7, 2017, and June 30, 2020, 41 696 patients were assessed for eligibility and 6944 (51.4 % female, 48.6% male; 97.7% self-reported European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided drug treatment (n=3342) or standard care (n=3602). 99 patients (52 [1.6%] of the study group and 47 [1.3%] of the control group) withdrew consent after group assignment. 652 participants (367 [11.0%] in the study group and 285 [7.9%] in the control group) were lost to follow-up. In patients with an actionable test result for the index drug (n=1558), a clinically relevant adverse drug reaction occurred in 152 (21 center dot 0%) of 725 patients in the study group and 231 (27.7%) of 833 patients in the control group (odds ratio [OR] 0 center dot 70 [95% CI 0 center dot 54-0 center dot 91]; p=0.0075), whereas for all patients, the incidence was 628 (21.5%) of 2923 patients in the study group and 934 (28. 6%) of 3270 patients in the control group (OR 0.70 [95% CI 0.61-0.79]; p <0.0001).Interpretation: Genotype-guided treatment using a 12-gene pharmacogenetic panel significantly reduced the incidence of clinically relevant adverse drug reactions and was feasible across diverse European health-care system organisations and settings. Large-scale implementation could help to make drug therapy increasingly safe.
|
|
| 6. |
- van der Wouden, Cathelijne H., et al.
(författare)
-
Generating evidence for precision medicine : considerations made by the Ubiquitous Pharmacogenomics Consortium when designing and operationalizing the PREPARE study
- 2020
-
Ingår i: Pharmacogenetics & Genomics. - 1744-6872 .- 1744-6880. ; 30:6, s. 131-144
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives Pharmacogenetic panel-based testing represents a new model for precision medicine. A sufficiently powered prospective study assessing the (cost-)effectiveness of a panel-based pharmacogenomics approach to guide pharmacotherapy is lacking. Therefore, the Ubiquitous Pharmacogenomics Consortium initiated the PREemptive Pharmacogenomic testing for prevention of Adverse drug Reactions (PREPARE) study. Here, we provide an overview of considerations made to mitigate multiple methodological challenges that emerged during the design.Methods An evaluation of considerations made when designing the PREPARE study across six domains: study aims and design, primary endpoint definition and collection of adverse drug events, inclusion and exclusion criteria, target population, pharmacogenomics intervention strategy, and statistical analyses.Results Challenges and respective solutions included: (1) defining and operationalizing a composite primary endpoint enabling measurement of the anticipated effect, by including only severe, causal, and drug genotype-associated adverse drug reactions; (2) avoiding overrepresentation of frequently prescribed drugs within the patient sample while maintaining external validity, by capping drugs of enrolment; (3) designing the pharmacogenomics intervention strategy to be applicable across ethnicities and healthcare settings; and (4) designing a statistical analysis plan to avoid dilution of effect by initially excluding patients without a gene–drug interaction in a gatekeeping analysis.Conclusion Our design considerations will enable quantification of the collective clinical utility of a panel of pharmacogenomics-markers within one trial as a proof-of-concept for pharmacogenomics-guided pharmacotherapy across multiple actionable gene–drug interactions. These considerations may prove useful to other investigators aiming to generate evidence for precision medicine.
|
|
| 7. |
- Makhado, T., et al.
(författare)
-
Chemical and electrochemical water oxidation mediated by bis(pyrazol-1-ylmethyl)pyridine-ligated Cu(i) complexes
- 2021
-
Ingår i: Sustainable Energy & Fuels. - : Royal Society of Chemistry (RSC). - 2398-4902. ; 5:10, s. 2771-2780
-
Tidskriftsartikel (refereegranskat)abstract
- Herein a series of novel bis(pyrazol-1-ylmethyl)pyridine-ligated Cu(i) complexes, C1-C4, bearing different donating groups [[H(C1), Me(C2), t-Bu(C3), Ph(C4)])] on the pyrazole rings, were synthesized and investigated as pre-catalysts in chemical and electrocatalytic water oxidation reactions. Ligands, 2,6-bis((1H-pyrazol-1-yl)methyl)pyridine (L1), 2,6-bis((1H-pyrazol-1-yl)methyl)pyridine (L2), 2,6-bis((3,5-di-tert-butyl-1H-pyrazol-1-yl)methyl)pyridine (L3), and 2,6-bis((3,5-diphenyl-1H-pyrazol-1-yl)methyl)pyridine (L4) were reacted with Cu(MeCN)(4)PF6 to form complexes C1-C4 respectively. Cerium ammonium nitrate (CAN), sodium m-periodate, and sodium persulfate were investigated as chemical oxidants in chemical water oxidation. Complexes C1-C4 showed catalytic activity towards chemical water oxidation in the presence of CAN as the primary oxidant at 25 degrees C. Complex C2 was the most active with a turnover number (TON) of 4.6 and a turnover frequency (TOF) of 0.31 s(-1). The least active catalyst was complex C4, with a TON of 2.3 and a TOF of 0.0086 s(-1). This observed difference in catalytic activity between the complexes illustrated the key role that electronic effects play during catalysis. Other oxidants evaluated with C2 were sodium m-periodate (TON, 3.77; TOF 0.14 s(-1)) and sodium persulfate (TON, 4.02; TOF 0.044 s(-1)) however, CAN exhibited the greatest activity. Complexes C1-C4 were investigated in electrocatalytic water oxidation at a neutral pH of 6.5. Complex C2 was the most active in electrocatalytic water oxidation as well, exhibiting an overpotential of 674 mV and TOF of 9.77 s(-1) (at 1.7 V vs. NHE), which is better than most reported copper(ii) complexes. These Cu(i) complexes C1-C4 show potential as efficient chemical and electrocatalytic water oxidation catalysts, which can be achieved by fine-tuning the steric and electronic properties of the catalysts.
|
|
