Plants sustain human life. Understanding geographic patterns of the diversity of species used by people is thus essential for the sustainable management of plant resources. Here, we investigate the... Show morePlants sustain human life. Understanding geographic patterns of the diversity of species used by people is thus essential for the sustainable management of plant resources. Here, we investigate the global distribution of 35,687 utilized plant species spanning 10 use categories (e.g., food, medicine, material). Our findings indicate general concordance between utilized and total plant diversity, supporting the potential for simultaneously conserving species diversity and its contributions to people. Although Indigenous lands across Mesoamerica, the Horn of Africa, and Southern Asia harbor a disproportionate diversity of utilized plants, the incidence of protected areas is negatively correlated with utilized species richness. Finding mechanisms to preserve areas containing concentrations of utilized plants and traditional knowledge must become a priority for the implementation of the Kunming-Montreal Global Biodiversity Framework. Show less
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... Show moreBackground 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, 41696 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 (21·0%) of 725 patients in the study group and 231 (27·7%) of 833 patients in the control group (odds ratio [OR] 0·70 [95% CI 0·54–0·91]; 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. Show less
Background: The clinical implementation of pharmacogenomics (PGx) could be one of the first milestones towards realizing personalized medicine in routine care. However, its widespread adoption... Show moreBackground: The clinical implementation of pharmacogenomics (PGx) could be one of the first milestones towards realizing personalized medicine in routine care. However, its widespread adoption requires the availability of suitable clinical decision support (CDS) systems, which is often impeded by the fragmentation or absence of adequate health IT infrastructures. We report results of CDS implementation in the large-scale European research project Ubiquitous Pharmacogenomics (U-PGx), in which PGx CDS was rolled out and evaluated across more than 15 clinical sites in the Netherlands, Spain, Slovenia, Italy, Greece, United Kingdom and Austria, covering a wide variety of healthcare settings. Methods: We evaluated the CDS implementation process through qualitative and quantitative process indicators. Quantitative indicators included statistics on generated PGx reports, median time from sampled upload until report delivery and statistics on report retrievals via the mobile-based CDS tool. Adoption of different CDS tools, uptake and usability were further investigated through a user survey among healthcare providers. Results of a risk assessment conducted prior to the implementation process were retrospectively analyzed and compared to actual encountered difficulties and their impact. Results: As of March 2021, personalized PGx reports were produced from 6884 genotyped samples with a median delivery time of twenty minutes. Out of 131 invited healthcare providers, 65 completed the questionnaire (response rate: 49.6%). Overall satisfaction rates with the different CDS tools varied between 63.6% and 85.2% per tool. Delays in implementation were caused by challenges including institutional factors and complexities in the development of required tools and reference data resources, such as genotype-phenotype mappings. Conclusions: We demonstrated the feasibility of implementing a standardized PGx decision support solution in a multinational, multi-language and multi-center setting. Remaining challenges for future wide-scale roll-out include the harmonization of existing PGx information in guidelines and drug labels, the need for strategies to lower the barrier of PGx CDS adoption for healthcare institutions and providers, and easier compliance with regulatory and legal frameworks. Show less
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... Show moreObjectives 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. Show less
