Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Impact des cytochromes P450 2D6 et 3A sur les paramètres pharmacocinétiques et pharmacodynamiques de l'oxycodone

L'oxycodone est respectivement N- et O-déméthylée par les CYP3A et 2D6. Nous avons évalué leur contribution dans la pharmacocinétique et pharmacodynamie de l'oxycodone, et notamment son efficacité antinociceptive, dans une étude randomisée contrôlée croisée chez 10 volontaires sains génotypés (2PM-IM, 6EM, 2UM pour le CYP2D6). Les 5 séances étaient: placebo, oxycodone 0,2 mg/kg 2h après quinidine 100 mg et/ou kétoconazole 400 mg et/ou placebo. La naloxone était injectée 2h après. La pharmacocinétique (suivie sur 24h), la pharmacodynamie (6h) et les phénotypes (CYP2D6 et 3A) ont été évalués. Après oxycodone, l'activité pharmacodynamique (analgésie, toxicité) est accrue chez les UM alors que ces effets sont réduits chez les PM-IM. Le kétoconazole augmente la magnitude des effets pharmacodynamiques et la quinidine les réduit. La naloxone renverse les effets observés. Le génotype pour le CYP2D6 et les interactions médicamenteuses via les CYP2D6/3A ont une influence majeure sur la cinétique, l'effet analgésique et la sécurité de l'oxycodone

Cytochromes P450 activity and functionality: biomarker of drug response and valuable tool for Precision Medicine

The variations in the activity and functionality of drug metabolizing enzymes and in particular cytochromes P450 (CYP) are major determinants of drug therapeutic outcomes as they impact on drug pharmacokinetics. This thesis aims to describe the crucial role of integrative methods assessing the impact of genetic and environmental factors on CYP activity to support safe and effective drug therapies and more broadly precision medicine. After an outline on precision medicine and its major component pharmacogenomics, the characteristics of CYPs and importance in the field are described. In vitro, in vivo, and in silico methods allowing studying drug metabolism and CYP activity are then presented, and in particular the Geneva cocktail for CYP phenotyping developed and validated in our laboratory. Applications for clinical research and clinical pharmacology are then exemplified by the centenary opioid oxycodone whose pharmacokinetics and pharmacodynamics were reappraised using in vitro, in vivo and in silico technologies. Our findings led to clinical recommendations fully applicable to precision medicine. Finally, we review the current evidence on the clinical impact of CYP activity variations from genetic and environmental origins on drug response, and in particular clinical applications of CYP testing in pain medicine and other relevant medical specialties

Vitamin D and glaucoma: a critical review of the literature

Primary open-angle glaucoma is a progressive optic neuropathy which can lead to irreversible blindness if untreated. A number of studies have been published suggesting a correlation between the level of serum vitamin D3 and glaucoma or intraocular pressure (IOP). The latter is known to be a major risk factor for glaucoma and is the main target of glaucoma treatment. We give a critical review of the literature, exploring what is known about this matter. While some studies report an inverse association between serum vitamin D3 and IOP, others do not confirm this finding. Similar divergent conclusions came from studies regarding the association between serum vitamin D3 and the presence or severity of glaucoma. The effect of vitamin D3 on IOP decrease has been attributed to both aqueous humor production and trabecular meshwork outflow pathway increase. Vitamin D3 has been shown to play a major role in reducing inflammation, modulating the immune response, and decreasing angiogenesis in the eye and in other organs. It has been suggested that, through its neuroprotective effect, vitamin D3 could be a protective factor for glaucoma and that vitamin D3 deficiency could explain glaucoma occurrence or severity in some patients. Other neurodegenerative diseases such as Alzheimer's disease and multiple sclerosis have been similarly related to vitamin D3 deficiency. 1 alpha,25(OH)(2) vitamin D3 (calcitriol) supplementation has been shown to be beneficial for lowering IOP in monkeys. Although the studies highlighted in this review show interesting results, their limitations underscore the need for both population-based studies and larger randomized controlled trial with vitamin D3 supplementation. The specific role of vitamin D3 in the pathology of glaucoma remains to be elucidated, together with the possible therapeutic benefit of vitamin D3 supplementation

CYP450 3A4/5 Containment During SARS-CoV-2 Infection

Comment on : Le Carpentier EC, Canet E, Masson D, Martin M, Deslandes G, Gaultier A, Dailly É, Bellouard R, Gregoire M. Impact of Inflammation on Midazolam Metabolism in Severe COVID-19 Patients. Clin Pharmacol Ther. 2022 Nov;112(5):1033-1039. doi: 10.1002/cpt.2698. Epub 2022 Jul 27. PMID: 35776074; PMCID: PMC9350233

Cyber harassment of female scientists will not be the new norm

International audienceWe read with interest the articles by Estella Ektorp1 and Nathan PeifferSmadja and colleagues,2 which reported receipt of death threats and cyber harassment in Brazil, France, and Switzerland after publication of studies that did not demonstrate clinical efficacy for chloroquine and hydroxychloroquine in COVID-19. We fully support our colleagues and feel concerned by what they report, having been victims ourselves-female professors of medicine-to varying degrees of threats of all kinds, including violent defamatory statements, stalking, and misogynistic and gender-oriente

Letter by Bouatou et al Regarding Article, "Polypharmacy and the Efficacy and Safety of Rivaroxaban Versus Warfarin in the Prevention of Stroke in Patients With Nonvalvular Atrial Fibrillation"

Letter to the Editor