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Aims: Our aim was to describe the pharmacokinetics of paracetamol and its metabolites in extreme preterm neonates in the context of patent ductus arteriosus treatment. Factors associated with inter-individual variability and metabolic pathways were studied. The association between drug exposure and clinical outcomes were investigated., Methods: Preterm neonates of 23-26 weeks' gestational age received paracetamol within 12 h after birth. Plasma concentrations of paracetamol and its metabolites were measured throughout 5 days of treatment. Clinical success was defined as ductus closure on two consecutive days or at day 7. Aspartate aminotransferase and alanine aminotransferase levels were used as surrogates for liver damage., Results: Data from 30 preterm neonates were available for pharmacokinetic analysis. Paracetamol pharmacokinetics were described using a two-compartment model with significant positive effects of weight on clearance and of birth length on peripheral compartment volume. Paracetamol was mainly metabolised into sulphate (89%) then glucuronide (6%), and the oxidative metabolic pathway was reduced (4%). The glucuronidation pathway increased with gestational age, whereas the sulfation pathway decreased. No difference was observed in drug exposure between successful and unsuccessful patients. No increase in aspartate aminotransferase and alanine aminotransferase levels were observed during treatment, and no association was found with either paracetamol or oxidative metabolite exposures., Conclusion: The relative proportions of the metabolic pathways were characterised with gestational age. In the range of observed drug exposures, no association was found with clinical response or liver biomarkers. These findings may suggest that paracetamol concentrations were within the range that already guarantee a maximum effect on ductus closure., Competing Interests: Declarations. Funding: Institut national de la santé et de la recherche médicale (Inserm) is the sponsor of the TREOCAPA trial. The project leading to this application has received funding through the Connect4Children consortium from the Innovative Medicines Initiatives 2 Joint Undertaking under grant agreement n°777389. This joint undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. Role of the funder/sponsor: The funding organisation had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. Conflict of interest: Faheemah Padavia, Jean-Marc Treluyer, Gilles Cambonie, Cyril Flamant, Aline Rideau, Manon Tauzin, Juliana Patkai, Géraldine Gascoin, Mirka Lumia, Outi Aikio, Frantz Foissac, Saïk Urien, Sihem Benaboud, Gabrielle Lui, Léo Froelicher Bournaud, Yi Zheng, Ruth Kemper, Marine Tortigue, Alban-Elouen Baruteau, Jaana Kallio, Mikko Hallman, Alpha Diallo, Léa Levoyer, Jean-Christophe Roze And Naïm Bouazza declare that they have no potential conflicts of interest that might be relevant to the contents of this manuscript. Ethics approval: The trial was approved by the ethics committee of Centre Hospitalier La Chartreuse (approval number SI 20.03.09.40128) for France and by the regional medical research ethics committee of North Ostrobothnia (approval number 68/06.00.00/20 19) for Finland. Consent to participate: Written informed consent was obtained from both parents of each infant. Consent for publication: Not applicable. Data availability statement: The data that support the findings of this study are available from Institut national de la santé et de la recherche médicale (Inserm) but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. However, data are available from the authors upon reasonable request and with permission from Inserm. Author contributions: Concept and design: NB, MH, JMT, JCR. Acquisition of data: GC, CF, AR, MT, JP, GG, ML, OA, YZ, MT, AEB. Analysis and interpretation of data: FP, NB, FF, SU, JCR. Drafting of the manuscript: FP, NB, FF, SU, GL, LFB, JCR. Critical revision of the manuscript for important intellectual content: All authors., (© 2024. The Author(s).)

Introduction: Increased salience of drug-related cues over nondrug reinforcers can drive drug use and contribute to tobacco use disorder (TUD). An important scientific and clinical goal is to effectively measure this elevated drug-seeking behavior in TUD. However, most TUD assessments rely on self-reported cravings and cigarette consumption, not providing an objective measure of the impact of drug cues on biasing behavior toward drugs. The probabilistic image choice (PIC) task investigates the choice of viewing drug-related pictures as compared to other salient pictures (eg, pleasant and unpleasant). This study aimed to develop and validate the PIC task for TUD and evaluate the associations between behavioral choice and tobacco craving, daily cigarette consumption, quit attempts and motivation to quit, and nicotine dependence (the Fagerström score)., Methods: We recruited 468 smokers and 121 nonsmokers using the Prolific online platform. Participants performed the PIC task twice (at a 1-month interval) and completed other measures relevant to TUD., Results: Compared to nonsmokers, tobacco smokers selected to view significantly more tobacco images and less pleasant (nondrug reinforcer) images, a profile that remained stable at retest. Individual differences in choice of tobacco as compared to pleasant images on the PIC task were associated with craving but not with the other tobacco dependence measures, suggesting that the task may serve as a behavioral proxy measure of drug "wanting" rather than of cumulative nicotine exposure or physical dependence., Conclusions: These results suggest that the PIC task can be a valuable tool for objectively assessing craving-associated tobacco seeking in TUD., Implications: Most of the current measures of TUD rely on self-reports of consumption, dependence, and craving, and do not take into consideration the role of drug-related cues in driving tobacco seeking. This study shows that the PIC task provides an objective, reliable proxy measure of tobacco image-seeking behavior in people who smoke cigarettes that is linked to craving (desire) for smoking but not to other measures of TUD. Therefore, the PIC task may be a useful complementary tool for the classification, diagnosis, and prognosis of TUD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

P2Y12 receptors on the platelet plasma membrane are targeted by several antiplatelets drugs. Although oligomerization and functioning of P2Y12 receptors depend on the membrane environment, little is known about their preferred membrane localization and the role of surrounding lipid composition, especially the arachidonic acids (ARA), which are abundant in platelets. Coarse-grained molecular dynamics simulations of platelet plasma membrane based on the lipidomics data were used to investigate the P2Y12 lipid environment and the involvement of ARA in its oligomerization in platelet plasma membranes. The platelet plasma membrane contains two types of lipids nanodomains: ordered, enriched in SM and cholesterol, and disordered, enriched in ARA-containing lipids. P2Y12 receptors prefer to localize in these ARA-rich domains and induce the sorting of the ARA-containing lipids in their vicinity. This ARA-rich environment promotes the oligomerization of P2Y12 receptors and stabilizes the protein-protein interfaces of oligomers. As summary, oligomerization of P2Y12 receptors is promoted in ARA-rich nano-domains of the platelet plasma membrane., Competing Interests: Declaration of competing interest Semen Yesylevskyy is an employee of Receptor.AI INC and has shares in Receptor.AI INC., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hair analysis for drugs has become extensively used for forensic investigation in recent years. To best interpret hair drug content in post-mortem conditions, the extent of external contamination by biological fluids, such as blood, must be taken into account to avoid false positive results. The present study evaluated opiates and opioids incorporation into hair from blood containing different concentrations of morphine (MOR), 6-mono-acetyl morphine (6-AM), codeine (COD), dihydrocodeine (DHC), tramadol (TRA), oxycodone (OXY), methadone (MET), 2-ethylidene-1,5-dimethyl-3,3- diphenyl pyrrolidine (EDDP), buprenorphine (BUP) and norbuprenorphine (NBUP). The hair strands contaminated by brief soaking into blood were stored at room temperature (RT) or at 4°C during 6 hours, 1, 3, 7 or 14 days. After decontamination by extensive washing, we show that all opiates and opioids were incorporated into hair within a few hours at RT and 4°C, without significant changes over time. The concentrations of opiates and opioids in hair reached the cut-off levels established by the Society of Hair Testing (SoHT) for therapeutic (MET, COD), or toxic or lethal (all other molecules) blood concentrations. The metabolite to parent drug concentration ratios were determined for NBUP/BUP, MOR/6-AM and EDDP/MET and could be helpful as indicators of blood external contamination., Competing Interests: Declaration of Competing Interest None, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Pragmatic randomized controlled trials are getting more interest to improve trials' external validity. This study aimed to assess how pragmatic the design of the self-labelled pragmatic randomised controlled trials in the manual therapy field is., Methods: We searched MEDLINE and the Cochrane Central Register of Controlled Trials for self-labelled pragmatic randomised controlled trials in the manual therapy field until January 2024 were included. Two independent reviewers collected and extracted data related to the intention of the trial, the rationale for the intervention, and specific features of the trial and performed an assessment using the PRECIS-2 tool., Results: Of 39 self-labelled pragmatic trials, the mean PRECIS-2 score was 3.5 (SD: 0.6). Choice of outcome measures, how the interventions were performed, the follow-up of the participants and how all the available data were included in the statistical analysis were the domains rated as most 'pragmatic'. Participants' eligibility, recruitment, and setting obtained lower scores. Less than 25% of the trials claimed that the aim was to investigate an intervention under real-world conditions and to make clinical decisions about its effectiveness. In the 21% of the sample the authors described neither the proof-of-concept of the intervention nor the state of previous studies addressing related research questions., Conclusions: Self-labelled pragmatic randomised controlled trials showed a moderately pragmatic attitude. Beyond the label 'pragmatic', the description of the intention of the trial and the context of every PRECIS-2 domain is crucial to understanding the real pragmatism of a trial., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Introduction: Cabotegravir, an integrase strand transfer inhibitor, and rilpivirine, an NNRTI, constitute the first long-acting (LA), injectable, two-drug ART regimen approved for the maintenance of virological suppression in persons living with HIV-1 (PLHIV). The aim of this study was to assess clinical effectiveness and tolerability of LA cabotegravir/rilpivirine in a real-world setting., Patients and Methods: We conducted a retrospective, single centre study, including all PLHIV receiving LA cabotegravir/rilpivirine as standard-of-care in our tertiary centre even if initiated in clinical trials., Results: Between 2014 and 2022, 126 PLHIV initiated LA cabotegravir/rilpivirine. All were ART-experienced, and 98.4% had a viral load (VL) of <50 copies/mL before LA cabotegravir/rilpivirine initiation. Median BMI at cabotegravir/rilpivirine initiation was 24 IQR (23-28). During a median follow-up of 9 months IQR (7-24), 27 patients discontinued cabotegravir/rilpivirine: 5 because of virological failure, 6 for adverse events, 11 for personal reasons unrelated to treatment tolerance and 5 for other reasons. Virological failure was not associated with a higher BMI, nor with weight gain during LA intramuscular (IM) cabotegravir/rilpivirine treatment, inadequate cabotegravir and rilpivirine concentrations, VL blips or the use of oral lead-in (OLI) or not. No drug resistance-associated mutation emerged. Adverse events leading to treatment interruption were injection-site pain (n = 3) and neuropsychological side effects (n = 3). A correlation between BMI and both cabotegravir and rilpivirine concentrations at 1 month post-initiation of LA-IM cabotegravir/rilpivirine was observed, with no impact of OLI., Conclusions: Data from this real-world cohort of PLHIV who received cabotegravir/rilpivirine LA injections suggest that this regimen is effective and well tolerated. Virological failures were not associated with the acquisition of resistance mutations., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The optimal hemoglobin threshold to guide red blood cell (RBC) transfusion for patients with acute myocardial infarction (MI) and anemia is uncertain., Objective: To estimate the efficacy of 4 individual hemoglobin thresholds (<10 g/dL [<100 g/L], <9 g/dL [<90 g/L], <8 g/dL [<80 g/L], and <7 g/dL [<70 g/L]) to guide transfusion in patients with acute MI and anemia., Design: Prespecified secondary analysis of the MINT (Myocardial Ischemia and Transfusion) trial using target trial emulation methods. (ClinicalTrials.gov: NCT02981407)., Setting: 144 clinical sites in 6 countries., Participants: 3492 MINT trial participants with acute MI and a hemoglobin level below 10 g/dL., Intervention: Four transfusion strategies to maintain patients' hemoglobin concentrations at or above thresholds of 10, 9, 8, or 7 g/dL. Protocol exceptions were permitted for specified adverse clinical events., Measurements: Data from the MINT trial were leveraged to emulate 4 transfusion strategies and estimate per protocol effects on the composite outcome of 30-day death or recurrent MI (death/MI) and 30-day death using inverse probability weighting., Results: The 30-day risk for death/MI was 14.8% (95% CI, 11.8% to 18.4%) for a <10-g/dL strategy, 15.1% (CI, 11.7% to 18.2%) for a <9-g/dL strategy, 15.9% (CI, 12.4% to 19.0%) for a <8-g/dL strategy, and 18.3% (CI, 14.6% to 22.0%) for a <7-g/dL strategy. Absolute risk differences and risk ratios relative to the <10-g/dL strategy for 30-day death/MI increased as thresholds decreased, although 95% CIs were wide. Findings were similar and imprecise for 30-day death., Limitation: Unmeasured confounding may have persisted despite adjustment., Conclusion: The 30-day risks for death/MI and death among patients with acute MI and anemia seem to increase progressively with lower hemoglobin concentration thresholds for transfusion. However, the imprecision around estimates from this target trial analysis precludes definitive conclusions about individual hemoglobin thresholds., Primary Funding Source: National Heart, Lung, and Blood Institute., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M24-0571.

Purpose: Understanding resistance to selective FGFR inhibitors is crucial to improve the clinical outcomes of patients with FGFR2-driven malignancies., Experimental Design: We analyzed sequential ctDNA, ± whole-exome sequencing, or targeted next-generation sequencing on tissue biopsies from patients with tumors harboring activating FGFR2 alterations progressing on pan-FGFR-selective inhibitors, collected in the prospective UNLOCK program. FGFR2::BICC1 Ba/F3 and patient-derived xenograft models were used for functional studies., Results: Thirty-six patients were included. In cholangiocarcinoma, at resistance to both reversible inhibitors (e.g., pemigatinib and erdafitinib) and the irreversible inhibitor futibatinib, polyclonal FGFR2 kinase domain mutations were frequent (14/27 patients). Tumors other than cholangiocarcinoma shared the same mutated FGFR2 residues, but polyclonality was rare (1/9 patients). At resistance to reversible inhibitors, 14 residues in the FGFR2 kinase domain were mutated-after futibatinib, only the molecular brake N550 and the gatekeeper V565. Off-target alterations in PI3K/mTOR and MAPK pathways were found in 11 patients, often together with on-target mutations. At progression to a first FGFR inhibitor, 12 patients received futibatinib or lirafugratinib (irreversible inhibitors), with variable clinical outcomes depending on previous resistance mechanisms. Two patients with TSC1 or PIK3CA mutations benefited from everolimus. In cell viability assays on Ba/F3 and in pharmacologic studies on patient-derived xenografts, irreversible inhibitors retained better activity against FGFR2 kinase domain mutations, with lirafugratinib active against the recalcitrant V565L/F/Y., Conclusions: At progression to FGFR inhibitors, FGFR2-driven malignancies are characterized by high intra- and interpatient molecular heterogeneity, particularly in cholangiocarcinoma. Resistance to FGFR inhibitors can be overcome by sequential, molecularly oriented treatment strategies across FGFR2-driven tumors., (©2024 The Authors; Published by the American Association for Cancer Research.)

Objective: In recent years, safety concerns about modafinil exposure during pregnancy have emerged. In particular, increased risks for major congenital anomalies (MCA) and impaired fetal growth were reported, although study results were conflicting. Our investigation aims to examine previously reported safety signals., Method: Multicenter case series based on data from 18 Teratology Information Services from 12 countries. Modafinil exposed pregnancies with an estimated date of birth before August 2019 were included in this study. For prospectively ascertained pregnancies, cumulative incidences of pregnancy outcomes, rate of nonchromosomal MCA in first trimester exposed pregnancies and percentiles of neonatal/infant weight and head circumference (HC) were calculated. Potential dose-dependent effects on fetal growth were explored by linear regression models. Retrospectively ascertained cases were screened for pattern of MCA and other adverse events., Results: One hundred and seventy-five prospectively ascertained cases were included, of which 173 were exposed at least during the first trimester. Cumulative incidences for live birth, spontaneous abortion and elective termination of pregnancy were 76.9% (95% CI, 68.0%-84.8%), 9.3% (95% CI, 5.0%-16.9%), and 13.9% (95% CI, 8.1%-23.1%), respectively. Nonchromosomal MCA was present in 3/150 live births, corresponding to an MCA rate of 2.0% (95%CI, 0.6%-6.1%), none were reported in pregnancy losses. Compared to reference standards, birth weight (BW) tended to be lower and neonatal HC to be smaller in exposed newborns (data available for 144 and 73 of 153 live births, respectively). In nonadjusted linear regression models, each 100 mg increase of average dosage per pregnancy day was associated with a decrease in standard deviation score (SDS) of -0.28 SDS (95% CI, -0.45 to -0.10) for BW and of -0.28 SDS (95% CI, -0.56 to 0.01) for HC. Screening of 22 retrospectively reported cases did not reveal any specific pattern of MCA or other adverse outcomes., Conclusion: The results do not indicate an increased risk of MCA after in utero exposure to modafinil, but a tendency toward lower BW and reduced neonatal HC. However, these findings should be regarded as preliminary. Until further studies allow for a definite conclusion, modafinil should not be used during pregnancy., (© 2023 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

This study aimed to assess the feasibility of applying two recent phase I meta-analyses methods to protein kinase inhibitors (PKIs) developed in oncology and to identify situations where these methods could be both feasible and useful. This ancillary study used data from a systematic review conducted to identify dose-finding studies for PKIs. PKIs selected for meta-analyses were required to have at least five completed dose-finding studies involving cancer patients, with available results, and dose escalation guided by toxicity assessment. To account for heterogeneity caused by various administration schedules, some studies were divided into study parts, considered as separate entities in the meta-analyses. For each PKI, two Bayesian random-effects meta-analysis methods were applied to model the toxicity probability distribution of the recommended dose and to estimate the maximum tolerated dose (MTD). Meta-analyses were performed for 20 PKIs including 96 studies corresponding to 115 study parts. The median posterior probability of toxicity probability was below the toxicity thresholds of 0.20 for 70% of the PKIs, even if the resulting credible intervals were very wide. All approved doses were below the MTD estimated for the minimum toxicity threshold, except for one, for which the approved dose was above the MTD estimated for the maximal threshold. The application of phase I meta-analysis methods has been feasible for the majority of PKI; nevertheless, their implementation requires multiple conditions. However, meta-analyses resulted in estimates with large uncertainty, probably due to limited patient numbers and/or between-study variability. This calls into question the reliability of the recommended doses., (© 2024 The Author(s). Research Synthesis Methods published by John Wiley & Sons Ltd.)

(R,S)-ketamine (ketamine) has rapid and sustained antidepressant (AD) efficacy at sub-anesthetic doses in depressed patients. A metabolite of ketamine, including (2R,6R)-hydroxynorketamine ((6)-HNKs) has been reported to exert antidepressant actions in rodent model of anxiety/depression. To further understand the specific role of ketamine's metabolism in the AD actions of the drug, we evaluated the effects of inhibiting hepatic cytochrome P450 enzymes on AD responses. We assessed whether pre-treatment with fluconazole (10 and 20 mg/kg, i. p.) 1 h prior to ketamine or HNKs (10 mg/kg, i. p.) administration would alter behavioral and neurochemical actions of the drugs in male BALB/cJ mice with a highly anxious phenotype. Extracellular microdialysate levels of glutamate and GABA (Glu ext , GABA ext ) were also measured in the medial prefrontal cortex (mPFC). Pre-treatment with fluconazole altered the pharmacokinetic profile of ketamine, by increasing both plasma and brain levels of ketamine and (R,S)-norketamine, while robustly reducing those of (6)-HNKs. At 24 h post-injection (t24 h), fluconazole prevented the sustained AD-like response of ketamine responses in the forced swim test and splash test, as well as the enhanced cortical GABA levels produced by ketamine. A single (2R,6R)-HNK administration resulted in prevention of the effects of fluconazole on the antidepressant-like activity of ketamine in mice. Overall, these findings are consistent with an essential contribution of (6)-HNK to the sustained antidepressant-like effects of ketamine and suggest potential interactions between pharmacological CYPIs and ketamine during antidepressant treatment in patients., Competing Interests: Declaration of competing interest DJD serves as a consultant for Lundbeck, Roche, and Servier. AMG serves as a consultant for Lundbeck and Servier. JM, IM-D, DJD, AMG, and CAD are named on provisional patent applications for the prophylactic use of ketamine and other compounds against stress-related psychiatric disorders. PZ, JH, RM, and TDG are co-inventors in patents and/or patent applications related to the pharmacology and synthesis, crystal structure and use of HNKs and related molecules for the treatment of addiction, depression, anxiety, anhedonia, suicidal ideation and post-traumatic stress disorders., (Copyright © 2024. Published by Elsevier Ltd.)

Clozapine is effective in treatment-resistant schizophrenia but with adverse effects including sedation. Excessive daytime sleepiness, a symptom of hypersomnolence, is the most frequently reported subjective side-effect. The aim of this systematic review was to synthesise the literature evaluating the impact of clozapine on the objective assessment of hypersomnolence in people with schizophrenia. We systematically searched databases for articles evaluating hypersomnolence with electrophysiological or psychomotor/cognitive measures in clozapine-treated patients with schizophrenia. Objective assessment of hypersomnolence was evaluated in six studies. All studies using polysomnography (PSG) found significantly longer total sleep time and shorter sleep onset latency in patients treated with clozapine at initiation of clozapine. The study with the multiple sleep latency test (MSLT) also found a shorter sleep onset latency. These observations did not persist 4-6 weeks after treatment initiation. Further investigations are needed. Longer total sleep time should be investigated with standardised long-term PSG to investigate excessive sleep quantity. Shorter sleep onset latency should be investigated with the MSLT or the maintenance of wakefulness test to investigate the excessive propensity to fall asleep or ability to stay awake. Lastly, sleep inertia should be investigated specifically in the morning., (© 2024 European Sleep Research Society.)

The French Addictovigilance Network has been using data from the French Heath insurance since the late 1990s to assess prescription drug abuse. In this narrative review, we illustrate the inputs of pharmacoepidemiology in addictovigilance based on the experience of the French Addictovigilance Network. The review focuses on pharmacoepidemiology using the French National Health Data System. We propose three examples: the MEGADOSE study, which aimed to conduct the first nation-wide, systematic, repeated assessment of doctor shopping; the DANTE study, which aimed to assess trends in analgesic use, focusing on the prevalence of use and the demographic profiles of analgesic users by age and sex; and the ZORRO study, which aimed to assess the impact of secure prescription forms on the use of zolpidem and other sedatives. These examples show how pharmacoepidemiology fits in the multifaceted monitoring conducted by the French Addictovigilance Network and complements the other data sources of this framework. This approach improves signal detection, confirmation, and quantification. It also makes it possible to overcome the limitations of each data source taken individually., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: Analgesics are among the most widely used drugs worldwide. The French Addictovigilance Network (FAN) established the antalgiques stupéfiants et ordonnances sécurisées (ASOS [narcotic analgesics and secure prescriptions]) survey in order to assess the dissemination of tamper-resistant prescription forms for narcotic analgesic within the medical community, as well as the nature and evolution of the prescriptions. After outlining the missions of the FAN, this article will describe the population treated with narcotic analgesics in France, their therapeutic indications and how the data have evolved since 2007., Methods: A cross-sectional, national, multicentre survey study was conducted that included surveys taken every year from 2007 to 2023 in a national sample of 1500 randomly selected dispensing pharmacies., Results: The mean age of patients, mostly women (around 60%), remained stable over the study period (63.2years in 2007, 67.6years in 2023). Most prescriptions involved morphine, oxycodone and fentanyl. Morphine and fentanyl were the reference molecules for prescribing opioid analgesics, but the sharp increase in oxycodone prescriptions between 2007 and 2015 impacted their usage. Cancer and rheumatologic pains were the main indications, with an increase in neurological indications in recent years. A focus on fentanyl and oxycodone highlights misuse patterns that are difficult to identify in other surveys., Conclusions: This study demonstrates how narcotic opioids are prescribed in France, thanks to the active participation of health professionals, and confirms the striking increase in the prescription of oxycodone and the misuse of fentanyl., (Copyright © 2024 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

This article proposes to trace back the timeline of the monitoring of falsified medical prescriptions in France as part of the French Addictovigilance System's toolbox. It examines the genesis of the OSIAP survey (Suspect Prescriptions Indicator of Possible Abuse), which has been held at the national level since 2001 but was created in the early 1990s, and its development until the current situation with a continuously confirmed yearly increasing trend. Understanding the birth and development of OSIAP and some other Addictovigilance tools that continue to be useful after more than 30 years of existence requires to review key historical benchmarks including the principles and missions of the former French National Commission on Narcotic and Psychotropic Drugs. Even though the OSIAP survey is part of a specific toolbox developed and routinely explored by the Addictovigilance network in a multidimensional approach, it has also been the sole data source, which identified some problematic drug uses, such as the early detection of tropicamide eye drop misuse in France or the diversion of codeine cough syrups after July 2017. Nevertheless, findings obtained from this data source should be checked against other complementary sources. Close monitoring of falsified prescriptions should be maintained in France, and the recent evolutions are plaid for supporting this survey. It is still being determined whether the constant increase of false prescription forms recorded in the OSIAP survey results from an increase in the absolute number of falsified prescriptions or whether pharmacists have become more vigilant with time. Still, the acceleration of these falsifications is also in line with the deployment of teleconsultations and the democratisation of digital techniques such as copying prescriptions or generating false QR codes. The forging techniques will likely evolve again in the future, possibly by adapting to stricter requirements such as the implementation of dematerialised prescriptions., Competing Interests: Disclosure of interest The authors declare that they have no competing interest., (Copyright © 2024. Published by Elsevier Masson SAS.)

France has several monitoring systems that form the foundation of its health safety surveillance. This system is designed for the early detection of signals and their swift into an action system that enables timely, appropriate, and effective interventions to protect public health. These signals are considered alerts when sufficiently validated after an initial risk assessment and if they represent a potential threat to public health, necessitating an appropriate response. The French Addictovigilance Network (FAN) was established specifically to address complications associated with the use of psychoactive substances (PAS), both medicinal and non-medicinal, excluding alcohol and tobacco. This system, unique in Europe, provides information on one of the most complex vigilance systems due to its scope, and the risks associated with it are becoming an increasingly significant public health issue. FAN is at the forefront of identifying potential signals. It has been working closely with regional partners since 1990, particularly through a multi-source approach that combines data from various sources, in collaboration with local professionals. After outlining the missions of the addictovigilance centres and the general principles of signal detection in addictovigilance, this article will present recent examples involving similar products but different identifications or modes of consumption: synthetic cannabinoids, nitazene, pregabalin, methylphenidate. These examples demonstrate that while there are regional disparities, the risk of occurrence in other French regions should not be overlooked, and information should be rapidly communicated at the national level for preventive action., (Copyright © 2024 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

The OPPIDUM program was first created in 1990. It is an annual, repeated, cross-sectional, nationwide, multicenter program. Data are provided directly from users of psychoactive substances (PAS) seen in substance abuse treatment facilities. The OPPIDUM program includes sociodemographic data, data on the first PAS used and leading to dependence, data on PAS use in the week prior the interview and the modality of use. The OPPIDUM program contributes to characterize patterns of SPA use and detect changes in modalities of use or/and in users profiles. It relies on the acceptability and adhesion of the growing number of participating substance abuse treatment facilities for more than 30years, giving informative data at the national and regional level. In 2023, the OPPIDUM program gathers data from about 117,822 participants describing 239,959 patterns of PAS use (with more than 5000 participants each year). In this article, we reviewed the success of the oldest program of the French Addictovigilance Network (history, development, evolution and contribution) for the assessment and surveillance of substance abuse., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Any surgical procedure carries a risk for venous thromboembolism (VTE), albeit variable. Improvements in medical and surgical practices and the shortening of care pathways due to the development of day surgery and enhanced recovery after surgery, have reduced the perioperative risk for VTE., Objective: A collaborative working group of experts in perioperative haemostasis updated in 2024 the recommendations for the Prevention of perioperative venous thromboembolism published in 2011., Methods: The addressed questions were defined by 40 experts (GIHP, SFAR, SFTH and SFMV) and formulated in a PICO format. They performed the literature review and formulated recommendations according to the Grading of GRADE system. Recommendations were then validated by a vote determining the strength of each recommendation. Of note, these recommendations do not cover all surgical specialties. Especially, thromboprophylaxis in cardiac surgery, neurosurgery and obstetrics is not addressed., Results: 78 recommendations were formalized into 17 sections, including patient-related VTE risk factors, types of surgery, extreme body weight, renal impairment, mechanical prophylaxis, distal deep vein thrombosis; 27 were found to have a high level of evidence (GRADE 1) and 41 a low level of evidence (GRADE 2) and 10 were expert opinion. All had strong agreement among the experts., Conclusions: These guidelines help to weigh the perioperative risk for VTE (which includes the risk associated to surgery and the patient-related risk) against the adverse effects of thromboprophylaxis, either pharmacological or mechanical. This includes particularly the bleeding risk induced by antithrombotic drugs as well as costs., (Copyright © 2024. Published by Elsevier Masson SAS.)

Introduction: Cefiderocol is a siderophore cephalosporin active in vitro against carbapenemase-producing Enterobacterales, including New Delhi metallo-β-lactamases (NDM-1). A significant impact of the size of bacterial inoculum on its efficacy has been described in vitro, the clinical impact of which is unclear. Here, we analyse the inoculum effect of cefiderocol against E. coli-NDM-1 in vitro and in a murine peritonitis model., Materials and Methods: Escherichia coli 62-pTOPO and its isogenic variant expressing NDM-1, 62-pTOPO-NDM, were constructed from a clinical strain. MICs and bactericidal kinetics were determined at standard (105 cfu/mL) and high inoculum (107 cfu/mL). The in vivo effect was assessed in a severe murine peritonitis model, comparing low (106 cfu/mL) and high (108 cfu/mL) inoculum. Survival rates, organ sterilization and bacterial counts in spleen and peritoneal fluid were compared., Results: Cefiderocol MICs for 62-pTOPO and 62-pTOPO-NDM at standard and high inoculum were 0.008, 2, 2 and 1024 mg/L, respectively. Bactericidal activity was not achieved in vitro for 62-pTOPO-NDM at high inoculum with high cefiderocol concentrations (16 mg/L). In vivo, for 62-pTOPO-NDM, no difference was found in survival, organ sterilization or bacterial counts between low and high inoculum. For 62-pTOPO, no difference was observed in survival, despite less organ sterilization and higher bacterial counts in organs with the high inoculum., Conclusion: A significant inoculum effect of cefiderocol was observed in vitro for 62-pTOPO and 62-pTOPO-NDM. However, the effectiveness of cefiderocol was not reduced in vivo with a high bacterial inoculum. In vitro inoculum effect of cefiderocol may not be clinically significant., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Dalbavancin is a lipoglycopeptide antibiotic with a wide spectrum of activity against Gram-positive bacteria, including MDR isolates. Its pharmacokinetic properties and administration patterns could be useful for the treatment of bone and joint infections, especially prosthetic joint infections (PJIs)., Introduction: We report the case of an 80-year-old man who experienced an acute periprosthetic joint infection of his right total knee arthroplasty (TKA). A DAIR procedure was done with tissue sampling, which allowed identification of a linezolid-resistant MDR S. epidermidis (LR-MDRSE) strain. The patient was then treated with dalbavancin (four injections)., Methods: We studied the phenotypic and genomic evolution of the strains and plasma through concentrations of dalbavancin at different points in time., Results: After four injections (1500 mg IV) of dalbavancin over a 6 month period, the dalbavancin MIC increased 4-fold. Calculated f AUC 0-24 /MIC ratios were 945, 1239 and 766.5, respectively, at Days 49, 71 and 106, assuming an MIC of 0.032 mg/L. The PFGE dendrogram revealed 97% similarity among all the isolates. These results suggest acquisition by the S. epidermidis strain of dalbavancin resistance when the patient underwent dalbavancin treatment. A 4-amino-acid deletion in the walK gene coinciding with the emergence of phenotypic resistance was revealed by WGS without any other relevant indels., Conclusions: Despite dalbavancin treatment with pharmacokinetic management, emerging dalbavancin resistance in S. epidermidis was observed, resulting in treatment failure. This outcome led to a prosthesis revision and long-term suppressive antibiotic therapy, with no recurrence of PJI after an 18 month follow-up., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: Epidermal necrolysis (EN), comprising Stevens-Johnson syndrome and toxic EN, is a rare and severe blistering reaction, mainly induced by drugs. Differences between paediatric and adult patients regarding incidence, causes and outcomes have been discussed but are based on a limited number of patients from small case series., Objectives: To directly compare the incidence, cause and prognosis of adult and paediatric EN., Methods: We used data from the French Health System Database (1 January 2013-31 December 2022). We identified adult and paediatric patients hospitalized for EN using the International Classification of Diseases, 10th Revision codes combined with validated algorithms. Outcomes were the incidence of EN; the presence of a suspected drug before EN onset (defined as a new drug dispensation from 5 to 56 days prehospitalization); and in-hospital mortality. To estimate the association between paediatric EN and the presence of a suspect drug, we computed a multivariable logistic regression with odd ratios (ORs). To estimate the association with mortality, we computed a multivariable Cox proportional hazard ratio (HR) model., Results: A total of 1440 patients [799 (55.5%) female] with EN were included, comprising 219 children and 1221 adults. Among children, the incidence of EN was 1.5 cases [95% confidence interval (CI) 1.3-1.7] per 1 million person-years vs. 2.6 cases (95% CI 2.5-2.7) in adults. Moreover, children had less chance of being given a culprit drug before the onset of EN [n = 93/219 (42.5%) vs. n = 829/1221 (67.9%)], with an adjusted OR of 0.43 (95% CI 0.32-0.59; P < 0.001), together with a better prognosis: the mortality rate in paediatric patients was 1.4% (95% CI 0.4-3.7) vs. 19.4% (95% CI 17.3-21.7) in adults. The adjusted HR for in-hospital mortality in children was 0.12 (95% CI 0.04-0.38; P < 0.001)., Conclusions: Paediatric EN appears to be rarer, with less chance of being caused by drugs and has a better prognosis than adult EN. These results suggest the existence of different underlying pathophysiological mechanisms and clinical particularities between adult and paediatric patients with EN., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objectives: Proton pump inhibitor (PPI) exposure can lead to hyponatraemia, which is a common cause of delirium. An association between PPI exposure and delirium without hyponatraemia has been suggested in the literature. We aimed to describe the association between reports of delirium and PPI exposure and to assess the association between PPI and delirium with and without hyponatraemia., Design: A descriptive and disproportionality analysis of claims data., Setting: World pharmacovigilance database VigiBase between 1 January 1991 and 9 February 2022., Primary and Secondary Outcome Measures: In the first part, we described reports of delirium for which involvement of a PPI or interactions of PPIs with other drugs were suspected. In the second part, delirium cases and non-cases were used to assess the disproportionality signal using the reporting OR (ROR) for the associations of PPI exposure with delirium or delirium/hyponatraemia co-events., Results: We identified 2395 reports of delirium in which involvement of PPI exposure was suspected. Omeprazole, esomeprazole and pantoprazole were the most frequently reported PPIs. Hyponatraemia was present in 11% of the reports. The disproportionality analysis included 1 264 798 reports of adverse drug reactions in patients using PPIs, including 19 081 reports of delirium. We did not find a disproportionality signal for the association between PPI use and delirium (ROR 0.89, 95% CI 0.87 to 0.91). We detected an association of PPI use with delirium/hyponatraemia co-events (ROR 1.53, 95% CI 1.41 to 1.65)., Conclusions: Most reports of delirium in which the involvement of PPIs was suspected did not include concomitant hyponatraemia. However, no significant signal of disproportionate reporting of delirium was observed for PPIs compared with other drugs, except in cases of delirium associated with hyponatraemia. Hyponatraemia may be the main mechanism linking PPI exposure with delirium, and this possibility should be further explored in prospective studies., Trial Registration Number: NCT05815550., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The use of synthetic data in pharmacology research has gained significant attention due to its potential to address privacy concerns and promote open science. In this study, we implemented and compared three synthetic data generation methods, CT-GAN, TVAE, and a simplified implementation of Avatar, for a previously published pharmacogenetic dataset of 253 patients with one measurement per patient (non-longitudinal). The aim of this study was to evaluate the performance of these methods in terms of data utility and privacy trade off. Our results showed that CT-GAN and Avatar used with k = 10 (number of patients used to create the local model of generation) had the best overall performance in terms of data utility and privacy preservation. However, the TVAE method showed a relatively lower level of performance in these aspects. In terms of Hazard ratio estimation, Avatar with k = 10 produced HR estimates closest to the original data, whereas CT-GAN slightly underestimated the HR and TVAE showed the most significant deviation from the original HR. We also investigated the effect of applying the algorithms multiple times to improve results stability in terms of HR estimation. Our findings suggested that this approach could be beneficial, especially in the case of small datasets, to achieve more reliable and robust results. In conclusion, our study provides valuable insights into the performance of CT-GAN, TVAE, and Avatar methods for synthetic data generation in pharmacogenetic research. The application to other type of data and analyses (data driven) used in pharmacology should be further investigated., (© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Attrition continues to be a major hurdle for addiction treatment. Through the prism of the attachment theory, this phenomenon can be understood as a manifestation of the patient's insecure attachment style, needing a highly-responsive care delivery. We developed an electronic health mobile application, co-designed with patients, aimed at helping healthcare teams respond to their patients' needs, and fostering adherence to care. This acceptability study evaluated patients everyday use of the application for eight weeks, assessing their satisfaction with the system, and its integration within professionals' current practice in our center., Methods: This single-center, prospective study was conducted between January 2022 and December 2022. 24 adult patients with any type of addiction were included. They were granted access to the application for eight weeks, and were invited to complete the System Usability Scale questionnaire regarding their satisfaction with application's usability at the end of the study. The application uses active self-reports, which are later discussed with the healthcare team, and foster both the working alliance and the decision-making process., Results: 17 patients out of 24 reached the primary endpoint. On average, over the eight-weeks period, patients logged in the application 38.2 times, and sent 5.9 messages to the healthcare team. Interestingly, 64.3% of the user logins were recorded outside of our center's working hours (either from 5 p.m. to 9 a.m., or during week-ends and bank holidays), and 70.8% of the patients logged into the application at least one time between 10 p.m. and 8 a.m. 18 patients completed the System Usability Scale questionnaire, which averaged a score of 81.8 out of 100. Healthcare professionals logged in the application's messaging system 4.5 times a day on average., Conclusions: This preliminary study shows promising results, as patients engaged well with various components of the application. It was moreover possible for healthcare workers in our center to integrate this tool in their daily activities. More work is needed to better understand the various patients' needs regarding the application, further strengthen their adherence to the intervention, and understand professionals' motivations to use the application., Trial Registration: ClinicalTrials.gov, Identifier: NCT04659954. Registered 09 December 2020, https://clinicaltrials.gov/study/NCT04659954 ., (© 2024. The Author(s).)

Background: A highly effective therapy involving elexacaftor, tezacaftor, and ivacaftor (ETI) for cystic fibrosis (CF) patients has recently raised safety concerns regarding potential psychiatric disorders. The manuscript reports cases of suicide attempts in patients receiving ETI and investigates putative causality using the WHO spontaneous reporting database., Methods: First, four cases of suicide attempts/self-injury are described. Second, a disproportionality analysis was conducted using spontaneous reports collected in Vigibase through the standardised MedDRA Query (narrow version) "Suicide/Self-injury" and ETI exposure. Reporting Odds Ratio (ROR) was calculated for the main and subgroup (i/suicide attempt, ii/suicidal ideation) analyses. Sensitivity analyses were performed with variations in exposure, to ivacaftor/lumacaftor to assess the intrinsic psychiatric risk of CF patients, and paracetamol as a positive control for suicide attempt and a negative one for suicidal ideation. Exposure to reduced-dose ETI was studied to evaluate the dose-gradient effect., Results: Four cases of suicide attempt/self-injury occurred 3 to 13 months after ETI initiation in CF patients and were reported to the Bordeaux Pharmacovigilance centre. Aside, in Vigibase, ETI is associated with an increased likelihood of reporting suicidal behaviour (ROR 2.5, 95 % CI[2.1; 2.8]). A signal of disproportionate reporting was found for the subgroup of suicide attempts (1.4, 95 % CI[1.2; 1.8]), unlike ivacaftor/lumacaftor, which was associated only with the risk of reporting suicidal ideation. Significant ROR values were also found for reduced-dose ETI for all psychiatric effects studied except suicide attempt., Conclusions: ETI exposure is related with increased reporting of suicidal behaviour. A potential dose-dependent effect merits further investigation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Julie Macey declares participation on a Data Safety Monitoring Board and Advisory Board for Vertex Pharmaceuticals. The other authors have nothing to declare., (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Introduction: Fluoroquinolones can cause severe collagen-associated adverse effects, potentially impacting the pulmonary connective tissue. We investigated the association between fluoroquinolones and spontaneous pneumothorax., Methods: A case-time-control study was performed using the nationwide French reimbursement healthcare system database (SNDS). Cases were adults ≥18 years admitted for spontaneous pneumothorax between 2017 and 2022. For each case, fluoroquinolone use was compared between the risk period immediately preceding the admission date (days -30 to -1), and three earlier reference periods (days -180 to -151, -150 to -121, -120 to -91), adjusting for time-varying confounders. OR estimates were corrected for potential exposure-trend bias using a reference group without the event (matched on age, sex, chronic obstructive pulmonary disease history, calendar time). Amoxicillin use was studied similarly to control for indication bias., Results: Of the 246 pneumothorax cases exposed to fluoroquinolones (63.8% men; mean age, 43.0±18.4 years), 63 were exposed in the 30-day risk period preceding pneumothorax and 128 in the reference periods. Of the 3316 amoxicillin cases (72.9% men; mean age, 39.4±17.6 years), 1210 were exposed in the 30-day risk period and 1603 in the reference ones. OR adjusted for exposure-trend and covariates was 1.59 (95% CI 1.14 to 2.22) for fluoroquinolones and 2.25 (2.07 to 2.45) for amoxicillin., Conclusion: An increased risk of spontaneous pneumothorax was associated with both fluoroquinolone and amoxicillin use, with an even higher association for amoxicillin. This strongly suggests the role of the underlying infections rather than a causal effect of the individual antibiotics and can be considered reassuring regarding a potential lung connective toxicity of fluoroquinolones., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Watersheds and estuaries are impacted by multiple anthropogenic stressors that affect their biodiversity and functioning. Assessing their ecological quality has consequently remained challenging for scientists and stakeholders. In this paper, we propose a multidisciplinary approach to identify the stressors in seven small French estuaries located in agricultural watersheds. We collected data from landscape (geography, hydrobiology) to estuary (pollutant chemistry) and fish individual scales (environmental signatures, proteomics). This integrative approach focused on the whole hydrosystems, from river basins to estuaries. To characterize each watershed, we attempted to determine the land use considering geographic indicators (agricultural and urbanised surfaces) and landscape patterns (hedges density and riparian vegetation). Juveniles of European flounder (Platichthys flesus) were captured in September, after an average residence of five summer months in the estuary. Analyses of water, sediments and biota allowed to determine the concentrations of dissolved inorganic nitrogen species, pesticides and trace elements in the systems. Environmental signatures were also measured in flounder tissues. These environmental parameters were used to establish a typology of the watersheds. Furthermore, data from proteomics on fish liver were combined with environmental signatures to determine the responses of fish to stressors in their environments. Differential protein abundances highlighted a dysregulation related to the detoxification of xenobiotics (mainly pesticides) in agricultural watersheds, characterized by intensive cereal and vegetable crops and high livestock. Omics also revealed a dysregulation of proteins associated with the response to hypoxia and heat stress in some estuaries. Furthermore, we highlighted a dysregulation of proteins involved in urea cycle, immunity and metabolism of fatty acids in several systems. Finally, the combination of environmental and molecular signatures appears to be a relevant method to identify the major stressors operating within hydrosystems., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jean Laroche reports financial support was provided by the “Agence de l'eau Loire-Bretagne” (AELB, project ECOEST)., (Copyright © 2024. Published by Elsevier Ltd.)

Pulsatile hemodynamics have been shown to be independent predictors of cardiovascular events. The aim of the current study was to describe four pulsatile hemodynamic markers in a large, well-established, population-based cohort and to provide reference equations for sex- and age-based standardization of these measurements. 6828 adult participants from the Austrian LEAD (Lung, hEart, sociAl, boDy) cohort study, who were free from overt cardiovascular disease, non-diabetic based on blood test results, and had no history of pharmacological treatment for hypertension, dyslipidemia, and diabetes, comprised the "reference population". Carotid-femoral pulse wave velocity (cfPWV), augmentation index (AIx), amplitude of forward wave (Pf), and backward wave (Pb) were described in different age categories for both sexes. Sex-specific reference equations for cfPWV, AIx, Pf, and Pb with age as the predictive variable were created using the Lambda-Mu-Sigma (LMS) method. All four parameters increased with age. CfPWV and Pf were higher in males than females, especially in young and middle-age groups (P < 0.001). AIx was higher in females than males in all age categories (P < 0.001). Pb was also higher in females than males in age groups older than 40 years (P < 0.01). Reference equations for the skewness (Lambda), median (Mu), and coefficient of variation (Sigma) values were determined, enabling the calculation of sex- and age-standardized values (z-scores) for each individual's pulsatile hemodynamic measurement, and an online application was developed. Reference equations derived from a large population-based dataset constitute a suitable tool for the standardization of pulsatile hemodynamics and for the accurate interpretation of vascular aging., (© 2024. The Author(s).)

Importance: The incidence of epidermal necrolysis (EN), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), varies across studies. While in-hospital mortality rates range from 15% to 20%, contributors to long-term mortality have been rarely evaluated and remain unknown., Objective: To assess the incidence of and compare factors associated with in-hospital mortality and postdischarge mortality and sequelae among patients with EN., Design, Setting, and Participants: This cohort study used French Health System data from January 1, 2013, to December 31, 2022, and included all adult patients (aged ≥18 years) with EN identified using International Statistical Classification of Diseases, Tenth Revision codes combined with a validated algorithm., Exposure: Epidermal necrolysis., Main Outcomes and Measures: Incidence, in-hospital mortality, postdischarge mortality, and sequelae were assessed as main outcomes. Factors associated with mortality were assessed using a multivariable Cox proportional hazards model., Results: A total of 1221 adult patients with EN (median [IQR] age, 66 [49-79] years; 688 females [56.3%]) were included. Incidence was 2.6 (95% CI, 2.5-2.7) cases per million person-years. The in-hospital mortality rate was 19% (95% CI, 17%-21%) and postdischarge mortality rate, 15% (95% CI, 13%-17%) for an overall mortality of 34% (95% CI, 31%-36%). In multivariable analysis, factors associated with in-hospital mortality were age (adjusted hazard ratio [AHR], 1.03 per year of age; 95% CI, 1.02-1.04 per year of age), history of cancer (AHR, 2.04; 95% CI, 1.53-2.72), dementia (AHR, 1.85; 95% CI, 1.12-3.07), liver disease (AHR, 1.81; 95% CI, 1.24-2.64), and EN severity (TEN vs SJS: AHR, 2.14; 95% CI, 1.49-3.07). Cancer, liver disease, and dementia remained associated with postdischarge mortality (AHR, 3.26 [95% CI, 2.35-4.53], 1.86 [95% CI, 1.11-3.13], and 1.95 [95% CI, 1.11-3.43], respectively). Conversely, EN initial severity was not associated with mortality after hospital discharge (TEN vs SJS: AHR, 0.95; 95% CI, 0.60-1.47), but acute complications remained associated (AHR, 2.14 [95% CI, 1.26-3.63] and 2.44 [95% CI, 1.42-4.18] for acute kidney injury and sepsis, respectively). The main sequelae were ophthalmologic and mood disorders., Conclusion: The findings of this cohort study suggest that although EN is a rare condition, it is associated with high rates of in-hospital and postdischarge mortality among patients who are older and have comorbid conditions. However, in contrast with in-hospital mortality, postdischarge mortality is not associated with EN initial severity but with acute in-hospital complications (eg, acute kidney injury and sepsis). Future studies are needed to construct models to estimate long-term outcomes and sequelae in patients with EN.

Background: Mycophenolate mofetil (MMF) has been used to treat interstitial lung disease (ILD), but mycophenolate (MPA) pharmacokinetics was not reported for this use. This ancillary study of the EVER-ILD protocol aimed at describing the pharmacokinetic variability of MPA using population modelling in ILD., Methods: Concentrations of MPA were measured during an 8-h course for 27 ILD patients treated with 1000 mg MMF b.i.d. Absorption, distribution and elimination of MPA were described using population compartment models with first-order transfer and elimination rate constants, while accounting for both absorption peaks using gamma absorption models., Results: The pharmacokinetics of MPA was best described using a two-compartment model and two gamma absorption models, model performances of this model were still similar to those of a one gamma absorption model. This pharmacokinetics seemed to be notably influenced by body weight, renal function and inflammatory status. The distribubtion value area under the concentration curve between two administrations of MMF was AUC 12  = 52.5 mg.h/L in median (interquartile range: 42.2-58.0 mg.h/L)., Conclusion: This is the first study reporting MPA pharmacokinetics in ILD. This pharmacokinetics appears to be similar to other indications and should be further investigated in future studies., (© 2024 The Author(s). Fundamental & Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of Société Française de Pharmacologie et de Thérapeutique.)

Background: Due to its psychoactive effects, ketamine has become a drug used for non-medical purpose., Objectives: To assess the latest trends in ketamine use among people with substance use disorder and to characterize its clinical complications using complementary health data sources of the French Addictovigilance Network., Methods: First, we extracted all reports involving ketamine from 2012 to 2021 from the database of the OPPIDUM program (i.e., a multicentric program conducted in collaboration with hundreds of substance abuse treatment facilities that collects data on drugs used by subjects with substance use disorders). We described the reports globally and the changes from 2012 to 2021. Second, we extracted all cases involving ketamine from July 2020 to December 2022 from the French National Pharmacovigilance Database (BNPV). We identified the cases related to ketamine use among people with substance use disorder and described them., Results: There was a 2.5-fold increase in the number of ketamine users with substance use disorder in the OPPIDUM program, from 35 (0.7%) subjects in 2012 to 89 (1.7%) subjects in 2021. There was an increase in the proportion of subjects who were daily users, had distress upon discontinuation, and presented addiction. There were 238 cases related to ketamine use among people with substance use disorder in the French National Pharmacovigilance Database from July 2020 to December 2022. Among them, 94 (39.5%) cases involved ketamine use disorder, 20 (8.4%) cases involved urinary tract and kidney symptoms, and 13 (5.5%) cases involved hepatobiliary symptoms., Conclusion: The trend observed over 10 years reflects the growth in ketamine use among people with substance use disorder, although it does not allow to estimate the rates of non-medical use of ketamine in the general population. Ketamine-induced uropathy and cholangiopathy are reported in ketamine users with substance use disorder, especially in case of repeated and/or prolonged use of high doses., (© 2024 The Authors. Fundamental & Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of Société Française de Pharmacologie et de Thérapeutique.)

Competing Interests: The authors declare no conflict of interest.

The management of acute pain focuses on a multimodal approach integrating both pharmacological and non-pharmacological treatments. In recent years, caution towards opioids has increased, with several studies showing that they are not necessarily more effective than non opioid analgesics for pain relief for musculoskeletal pain, which is the most common painful symptom in outpatient settings, and have the disadvantages of more side effects and a risk of dependence. Adjuvant and non-pharmacological treatments (e.g. manual medicine, acupuncture, hypnosis) are gaining importance to reduce therapeutic escalation and improve pain management. This approach which can be more personalized, aims to minimize risks while ensuring effective relief of acute pain., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Cystic fibrosis is one of the most common genetic diseases among caucasian population. This disease is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding for the CFTR protein. Lumacaftor, elexacaftor, tezacaftor, and ivacaftor were currently used as the treatment to Cystic fibrosis. In this study, we describe a new method for the simultaneous quantification of four molecules: lumacaftor, elexacaftor, tezacaftor, and ivacaftor, alongside two metabolites of ivacaftor, specifically hexyl-methyl ivacaftor and ivacaftor carboxylate by liquid chromatography-tandem mass spectrometry. This method holds significant utility for therapeutic drug monitoring and the optimization of treatments related to CFTR modulators. Molecules were extracted from 100 µL of plasma by a simple method of protein precipitation using acetonitrile. Following extraction, chromatographic separation was carried out by reverse chromatography on a C18 analytical column, using a gradient elution of water (0.05 % formic acid, V/V) and acetonitrile (0.05 % formic acid, V/V). The run time was 7 minutes at a flow rate of 0.5 mL/min. After separation, molecules were detected by electrospray ionization on a Xevo TQD triple-quadrupole-mass-spectrometer (Waters®, Milford, USA). The calibration range were: 0.053-20.000 mg/L for elexacaftor, tezacaftor and lumacaftor, 0.075-14.000 mg/L for ivacaftor, and 0.024-6.500 mg/L for hexyl-methyl ivacaftor and ivacaftor carboxylate. The proposed method underwent throughout validation demonstrating satisfactory precision (inter- and intra-day coefficients of variation less than 14.3 %) and a good accuracy (inter- and intra-day bias ranging between -13.7 % and 14.7 %) for all the analytes. The presented method for the simultaneous quantification of CFTR modulators and their metabolites in human plasma has undergone rigorous validation process yielding good results including strong precision and accuracy for all analytes. This method has been effectively used in routine analytical analysis and clinical investigations within our laboratory., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: PARP inhibitors (PARPi) are used in the treatment of ovarian, breast, pancreatic, and prostate cancers. Pneumonitis has been identified as a potential side effect, with a higher meta-analysis-assessed risk for olaparib versus other PARPi. Olaparib-induced interstitial lung disease (O-ILD) was first described within the Japanese population, with few information available for Caucasian patients., Methods: We performed a retrospective study by pooling data from the French and Belgian pharmacovigilance databases from 2018 to 2022. Patients with O-ILD were included following a central review by: 1) pharmacologists using the French drug causality assessment method; 2) senior pneumologists or radiologists, using the Fleischner Society's recommendations., Results: Five patients were identified and analysed. All were females, with ovarian or breast cancer. Median age at O-ILD diagnosis was 71 (38-72) years old, with no smoking history. Median delay between treatment initiation and symptom occurrence was 12 (6-33) weeks. Pneumonitis severity assessed using the Common Terminology Criteria for Adverse Events V5 was Grade 3 (n = 4) or 2 (n = 1). CT-scan review (n = 3) described hypersensitivity pneumonitis reaction as a common pattern. Bronchioalveolar lavage (n = 4) revealed lymphocytic alveolitis. Treatments relied on olaparib discontinuation (n = 5) and glucocorticoid intake (n = 4), with no fatal issue. Safe re-challenge with PARPi occurred in two patients. Forty additional O-ILD cases were identified in the WHO VigiBase database, including one fatal case., Conclusions: PARPi-ILD is a rare but potentially life-threatening disease, presenting as a hypersensitivity pneumonitis pattern within 3 months of PARPi initiation. Treatment primarily relies on medication discontinuation. Re-challenging with another PARPi could be considered., Clinical Trial Number: CEPRO #2023-010., (© 2024. The Author(s).)

Using a new red blood cell (RBC) metabolite extraction protocol, we performed a metabolomic analysis on RBCs in rheumatoid arthritis (RA) patients treated or not with methotrexate (MTX), with the two following objectives: to compare the RBC metabolic profiles of MTX-naïve RA patients and healthy controls (HC), and to investigate whether RBC profiles before and after MTX treatment in RA differed between responders and non-responders. Plasma analysis was performed in parallel. Metabolites were extracted and identified in RBCs and plasma by liquid chromatography-mass spectrometry. We compared the metabolomic fingerprints of 31 DMARD-naïve RA patients and 39 HCs. We also compared the RBC and plasma metabolomes of 25 RA patients who responded or not to MTX therapy before (M0) and after a 3-month treatment period (M3). Significance was determined by Storey's false discovery rate (FDR) q-values to correct for multiple testing. RA patients and HCs differed in the metabolomic signature of RBCs. The signature mainly contained amino acids (AA). Eleven metabolites, including 4 metabolites belonging to the carbohydrate subclass and 2 amino acids (creatine and valine) showed accumulation in RBCs from RA patients. Conversely, citrulline (fold change = 0.83; q = 0.025), histidine (fold change = 0.86; q = 0.014) and ergothioneine (EGT) (fold change = 0.66; q = 0.024), were lower in RBC of RA patients. Five plasma metabolites, including succinic acid and hydroxyproline, were higher in RA patients, and 7 metabolites, including DHEA sulfate, alanine, threonine and ornithine, were lower. Among RA patients undergoing MTX treatment pre-treatment (M0), EGT values were significantly lower in non-responders. In conclusion, low RBC levels of EGT, a food-derived AA barely detectable in plasma, characterize DMARD naïve RA patients and lack of response to MTX treatment., (© 2024. The Author(s).)

Background: One major barrier to HIV cure is the persistence of virus, possibly linked to an insufficient antiretroviral drug (ARV) distribution into tissues., Objectives: To draw the whole-body distribution of three antiretroviral drugs-tenofovir disoproxil fumarate, emtricitabine and dolutegravir-in non-human primates (NHPs)., Methods: Eight uninfected NHPs received a single injection of a solution containing the three ARVs. Forty-five different tissues were sampled 24 h after injection., Results: Median tissue penetration factors (TPFs) were 45.4, 5.8 and 0.5 for tenofovir, emtricitabine and dolutegravir, respectively, and were statistically different between the three ARVs. Tissues were grouped by system, because TPFs were consistent according to these groups, and ranked in order of decreasing TPFs. The digestive system was the system with the highest tissue concentrations. Next came the two main sites of elimination, the liver and the kidney, as well as the tissues of the cardiopulmonary and urinary systems. Then, it was the whole lymphatic system. The next group included the reproductive system, the adipose tissue and the skin. The last two systems were the muscle and the CNS. The intra-tissue variability was rather low with a median coefficient of variation of the concentrations around 15% and no value greater than 80%., Conclusions: Overall, this study determines the first whole-body distribution in a validated NHP model. These data have important implications for future preclinical and clinical studies for the development of novel HIV therapies towards an HIV cure., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: The use of Complementary Alternative Medicine (CAM) in patients with cancer is increasing. CAM is associated with potential toxicity and drug interactions, particularly with chemotherapy. Here, we report a case of cytolysis and hepatic cholestasis in a patient who was self-medicated with a mushroom powder-based alternative therapy containing Agaricus blazei Murril (ABM) during cancer treatment., Case Report: A 43-year-old woman with metastatic colorectal cancer and hepatic metastases was admitted to our hospital for intravenous chemotherapy. Markers of hepatic grade 3 cytolysis and cholestasis were identified during the pretreatment consultation. The baseline results were within normal limits., Management and Outcome: The chemotherapy was immediately canceled, and further tests were performed. After the investigation, the patient reported taking three mushroom powder-based capsules per day since November 2023. The dietary supplement contained ABM and Hericium erinaceus (HE) powder. After Pharmaceutical analysis, treatment with the supplement was discontinued, and the patient has not resumed. The changes in liver function were also favorable., Discussion: In our case, given the improvement in liver function after CAM discontinuation, hepatic cytolysis appeared to be linked to ABM consumption despite the patient's liver metastases. Pharmaceutical analysis of CAM is essential to ensure the safety and optimization of cancer treatments. Patients should also communicate their CAMs to healthcare professionals and be aware of the consequences of consuming these dietary supplements. Finally, collaboration between pharmaceutical teams and oncologists is essential for optimal management of cancer patients., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Cannabinoid hyperemesis syndrome is characterized by recurrent episodes of severe nausea and vomiting, often associated with prolonged and excessive cannabis use. With the recent legalization and rising consumption of cannabidiol (CBD) in Europe and the United States, concerns have emerged about its potential role in triggering similar symptoms., Case Report: A 32-year-old male with a history of cannabis, tobacco and alcohol use disorder experienced multiple cyclic vomiting episodes after switching from cannabis to CBD. Initially, the patient presented with abdominal pain and vomiting after ceasing cannabis use, with symptoms alleviated by hot showers. Three months later, similar symptoms reappeared despite abstinence from cannabis but regular CBD consumption. Over the next 6 months, recurrent episodes of abdominal pain and vomiting persisted with daily CBD use but no cannabis consumption. Clinical data, laboratory results, and treatment responses were analyzed to investigate the connection between CBD consumption and symptom onset., Discussion: The pathophysiology of cannabis-induced cyclic vomiting is poorly understood. Hypotheses include tetrahydrocannabinol accumulation in adipose tissue, pyrolytic conversion of CBD into tetrahydrocannabinol, and CBD's intrinsic effects, particularly its interaction with transient receptor potential vanilloid 1 receptors. Our analysis suggests that high doses of CBD may activate transient receptor potential vanilloid 1 receptors, inducing proemetic effects., Conclusions: Although the connection between CBD and cyclic vomiting remains uncertain, it warrants further investigation. The increasing use of CBD, perceived as a safe dietary supplement, underscores the need to understand its potential health impacts better., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 American Society of Addiction Medicine.)

Recent research suggests that fetal exposure to antidepressants (ADs) is significantly associated with fetal death, including stillbirth. However, there has been limited investigation into the timing of AD exposure during pregnancy, the specific effect of each drug, and the possibility of indication bias. To address these gaps in knowledge, we conducted a systematic review of literature and disproportionality analyses using the WHO Safety Database (VigiBase Ⓡ ). The systematic review provided evidence for increased risks of fetal death with exposure to any selective serotonin reuptake inhibitor (SSRI) at any time of pregnancy, stillbirth with exposure to any AD during the first trimester, and stillbirth with exposure to any SSRI during the first trimester. Disproportionality analyses revealed significant associations with citalopram, clomipramine, paroxetine, sertraline, and venlafaxine. Combining both sets of results, we conclude that exposure to ADs, especially during the first trimester of pregnancy, seems to be associated with fetal mortality, and that ADs with highest placental transfer may be particularly involved. Further research should investigate the links between ADs during early pregnancy and fetal mortality., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The number of elderly people with type 2 diabetes (T2D) is increasing worldwide. Community pharmacies, thanks to their proximity, provide more easy access to therapeutic education for rural patients. Populations living in isolated areas require specific educational resources related to their condition. The aim of this project was to perform a short (FLASH) educational intervention, coordinated by community pharmacists, and then evaluate the impact of this intervention on patient knowledge of their disease. The study was performed in Issoudun, a rural French town of approximately 10,000 inhabitants. Educational priorities were defined and the project was presented to health authorities and local health professionals. Pharmacies in Issoudun recruited patients, either alone or accompanied by their caregivers. The educational intervention lasted 2h and focused on 4 teaching objectives: knowledge concerning diabetes, diabetic complications and how to monitor them; how to react to hypoglycemia; understanding treatments; and understanding glycated hemoglobin. The impact of this educational intervention was assessed using a questionnaire delivered before the intervention, immediately after, and after 6months. Forty-five patients aged 71±6years with T2D duration of 14±6years were recruited over 6months. Some false beliefs were identified before the intervention. The educational session led to a significant improvement in the percentage of correct answers (before: 60.3%±7.5, after: 99%±0.4, P=0.0002) and at 6months (99.5%±0.3, P=0.0002) compared with the patients' initial knowledge. Almost all false beliefs were corrected by the intervention and patients were able to recall the mechanism of action of their drugs, with the help of a "key and lock" schematic. This short FLASH educational intervention, coordinated by community pharmacists, showed that the model was both interesting to patients and effective. This method could be expanded to other rural communities and medical deserts., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)