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Martin Dres,1,2 Pierre Hausfater,3,4 Frantz Foissac,5,6 Maguy Bernard,7 Luc-Marie Joly,8 Mustapha Sebbane,9 Anne-Laure Philippon,3,4 Cédric Gil-Jardiné,10 Jeannot Schmidt,11 Maxime Maignan,12 Jean-Marc Treluyer,13 Nicolas Roche14,15 On behalf of the UTAPE Study Investigators and Scientific Committee 1Pulmonary and Critical Care Department, Pitié-Salpêtrière Hospital, AP-HP, 2UMRS1158: Clinical and Experimental Respiratory Neurophysiology, Paris 6 University, 3Emergency Department, Hôpital Pitié-Salpêtrière, AP-HP, 4Sorbonne Universités UPMC Univ-Paris06, GRC-14 BIOSFAST, 5Clinical Research Department, Necker Cochin Hospital, AP-HP, 6EA 7323, Sorbonne Paris-Cité, 7Biochemistry Department, Pitié-Salpêtrière Hospital, AP-HP, Paris, 8Emergency Department, Charles Nicolle Hospital, Rouen, 9Department of Emergency Medicine, Lapeyronie Hospital, Montpellier, 10Emergency Department, Pellegrin Hospital, Bordeaux, 11Emergency Department, Gabriel Montpied Hospital, Clermont-Ferrand, 12Emergency Department, Grenoble University Hospital, Grenoble, 13Clinical Research Department, Paris Descartes University, Hôpital Cochin, AP-HP, 14Pulmonary Department, Cochin Hospital, AP-HP, 15Paris Descartes University, Paris, France Background: Exacerbations of COPD (ECOPD) are a frequent cause of emergency room (ER) visits. Predictors of early outcome could help clinicians in orientation decisions. In the current study, we investigated whether mid-regional pro-adrenomedullin (MR-proADM) and copeptin, in addition to clinical evaluation, could predict short-term outcomes.Patients and methods: This prospective blinded observational study was conducted in 20 French centers. Patients admitted to the ER for an ECOPD were considered for inclusion. A clinical risk score was calculated, and MR-proADM and copeptin levels were determined from a venous blood sample. The composite primary end point comprised 30-day death or transfer to the intensive care unit or a new ER visit.Results: A total of 379 patients were enrolled in the study, of whom 277 were eventually investigated for the primary end point that occurred in 66 (24%) patients. In those patients, the median (interquartile range [IQR]) MR-proADM level was 1.02 nmol/L (0.77–1.48) versus 0.83 nmol/L (0.63–1.07) in patients who did not meet the primary end point (P=0.0009). In contrast, copeptin levels were similar in patients who met or did not meet the primary end point (P=0.23). MR-proADM levels increased with increasing clinical risk score category: 0.74 nmol/L (0.57–0.89), 0.83 nmol/L (0.62–1.12) and 0.95 nmol/L (0.75–1.29) for the low-, intermediate- and high-risk categories, respectively (P

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).)

Background: Pregnancy-associated haematological malignancy is a rare event; therefore, data available to guide the treatment are scarce. We aimed to evaluate the incidence, overall survival, and maternal morbidity and mortality of women with pregnancy-associated haematological malignancies., Methods: We conducted a nationwide observational cohort study using the French National Healthcare Data System (SNDS), a health-care administrative database covering up to 99% of the French population. We included all pregnancies in France ending between Jan 1, 2012, and Dec 31, 2022. Pregnancies with terminations or miscarriages managed on an outpatient basis, and women with a history of haematological malignancies before pregnancy were excluded. A Cox proportional hazards model was used to assess overall survival, defined as the date of haematological malignancy diagnosis to either death or the end of the study follow-up, in the haematological malignancy during pregnancy group (pregnancies with a diagnosis of haematological malignancy during pregnancy) compared with the haematological malignancy post-pregnancy group (pregnancies with a diagnosis of haematological malignancy in the year following pregnancy). Severe maternal morbidity was compared in the haematological malignancy during pregnancy group versus the reference group (pregnancies without a history of haematological malignancy or a diagnosis of pregnancy-associated haematological malignancy). Births were classified as very preterm (<32 weeks of pregnancy), preterm (32-36 weeks), and term (≥37 weeks) and compared in the haematological malignancy during pregnancy group versus the reference group. Inverse probability weighting (IPW) was used for confounder adjustment, using maternal age (categorised), comorbidities, socioeconomic status, and year of delivery (as a category)., Findings: Of 9 996 523 pregnancies in 5 995 235 women, 1366 pregnancy-associated haematological malignancies were identified: 413 during pregnancy (4·13 per 100 000 pregnancies) and 953 (9·53 per 100 000 pregnancies) within 12 months of the end of pregnancy (post-pregnancy). No significant differences in overall survival were observed between the haematological malignancy during and post-pregnancy groups across all types of haematological malignancy (IPW-adjusted hazard ratio 0·91 [95% CI 0·62-1·34], p=0·63), specifically for Hodgkin lymphoma (0·56 [0·07-4·53], p=0·59), aggressive B-cell non-Hodgkin lymphoma (0·52 [0·12-2·38], p=0·40), and acute leukaemia alone (0·84 [0·50-1·41], p=0·51). Severe maternal morbidity was more frequent in the haematological malignancy during pregnancy group than in the reference group (86 [26·2%] of 328 completed pregnancies vs 120 335 [1·5%] of 7 945 909 completed pregnancies; IPW-adjusted odds ratio 22·71 [95% CI 17·72-29·10], p<0·0001). We observed an increase in very preterm birth (32 [9·8%] vs 92 712 [1·2%]; IPW-adjusted odds ratio 11·90 [95% CI 7·91-17·91], p<0·0001) and preterm birth (116 [35·4%] vs 430 472 [5·4%]; 11·76 [9·34-14·81], p<0·0001) in the haematological malignancy during pregnancy group compared with the reference group., Interpretation: This nationwide observational study examines pregnancy-associated haematological malignancies in France, revealing no significant difference in overall survival between women diagnosed during pregnancy and post-pregnancy. Our data highlight an increased frequency of severe maternal morbidity and obstetric complications among women diagnosed during pregnancy. Notably, the study underscores the necessity for specialised care to manage these complex cases effectively., Funding: None., Translation: For the French translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests CC declares consulting fees from Pfizer. LH declares support for attending meeting from Servier. NB is an unpaid member of the French Birth Defects Scientific Expert Committee (Santé Publique France). RB declares consulting fees from Bristol Myers Squibb, honoraria for presentations form Jazz Pharma, and support for attending meetings from Sandoz. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

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.)

Aims: Population pharmacokinetics (PK) models may be effective in improving antibiotic exposure with individualized dosing. The aim of the study is to assess cefazolin exposure using a population PK model in critically ill children., Methods: We conducted a single-centre observational study including children under 18 years old who had cefazolin plasma monitoring before and after a cefazolin model implementation. The first concentration at steady state of each cefazolin course was analysed. The optimal exposure was defined by concentration values ranging from free concentration over four times the minimal inhibitory concentration (MIC) for 100% of the dosing interval to total trough or plateau concentration under 100 mg. L -1 ., Results: A total of 58 patients were included, of whom 39 and 19 children received conventional dosing or model-informed dosing, respectively. Median [range] age was 2.3 [0.1-17] years old, and median weight was 14.2 [2.9-72] kg. There were more continuous infusions (CI) in the model group than in the conventional group (n = 19/19 [100%] vs. n = 23/39 [59%]). Compared to conventional dosing, model-informed dosing provided more optimal exposure (n = 17/39 [44%] vs. n = 15/19 [79%], P = .01) and less underexposure (n = 18/39 [46%] vs. n = 2/19 [10%], P = .008), without increasing overexposure (n = 4/39 [10%] vs. n = 2/19 [11%], P = 1). Moreover, the time to C-reactive protein decrease by 50% was significantly shorter in the model group than the conventional group (3 [0.5-13] vs. 4 [1-34]; P = .045)., Conclusions: Use of individualized cefazolin model-informed dosing improves critically ill children's exposure. Further studies are needed to assess the clinical benefit of cefazolin PK model application., (© 2024 British Pharmacological Society.)

Aims: Vigabatrin is an antiepileptic drug used to treat some forms of severe epilepsy in children. The main adverse effect is ocular toxicity, which is related to the cumulative dose. The aim of the study is to identify an acceptable exposure range, both through the development of a population pharmacokinetic model of vigabatrin in children enabling us to calculate patient exposure and through the study of therapeutic response., Methods: We performed a retrospective study including children with epilepsy followed at Necker-Enfants Malades hospital who had a vigabatrin assay between January 2019 and January 2022. The population pharmacokinetic study was performed on Monolix2021 using a nonlinear mixed-effects modelling approach. Children treated for epileptic spasms were classified into responder and nonresponder groups according to whether the spasms resolved, in order to identify an effective plasma exposure range., Results: We included 79 patients and analysed 159 samples. The median age was 4.2 years (range 0.3-18). A 2-compartment model with allometry and creatinine clearance on clearance best fit our data. Exposure analysis was performed on 61 patients with epileptic spasms. Of the 22 patients who responded (36%), 95% had an AUC 0-24 between 264 and 549 mg.h.L -1 ., Conclusions: The population pharmacokinetic model allowed us to identify bodyweight and creatinine clearance as the 2 main factors explaining the observed interindividual variability of vigabatrin. An acceptable exposure range was defined in this study. A target concentration intervention approach using this pharmacokinetic model could be used to avoid overexposure in responder patients., (© 2024 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Introduction and Objective: Given the high prevalence of antibiotic prescription during pregnancy in France and previous studies suggesting an increased risk of infection in offspring with such exposures, our study aimed to investigate the association between prenatal exposure to systemic antibiotics and serious infections in full-term infants during their first year of life., Methods: We conducted a retrospective population-based cohort study on singleton, full-term liveborn non-immunocompromised infants, using the French National Health Data System (SNDS) between 2012 and 2021. Systemic antibiotic dispensing in ambulatory care settings during pregnancy defined the exposure. Outcomes concerned serious infections (i.e., infections requiring hospitalization) in offspring identified between 3 and 12 months of life, hence excluding infections of maternal origin. Adjusted odds ratios (aORs) were estimated using logistic regression with multivariate models to control for potential confounders., Results: Of 2,836,630 infants included, 39.6% were prenatally exposed to systemic antibiotics. Infants prenatally exposed to antibiotics had a higher incidence of serious infections compared with unexposed infants {aOR 1.12 [95% confidence interval (95% CI) 1.11-1.13]}. Similar associations were observed according to the timing of exposure during pregnancy, antibiotic class, and site of infections. The strongest association was observed when infants were prenatally exposed to three or more antibiotic courses during pregnancy [aOR 1.21 (95% CI 1.19-1.24)]. Limitations include residual confounders, such as genetic susceptibility to infections and the role of the underlying pathogen agent., Conclusion: Prenatal exposure to systemic antibiotics is very common and is associated with a weak yet significant associations with subsequent serious infectious events during the first year of life. While our study revealed associations, it is important to note that causation cannot be established, given the acknowledged limitations, including potential confounding by indication., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Studies on drug utilization in western countries disclosed that about nine over ten women use at least one or more drugs during pregnancy. Determining whether a drug is safe or not in pregnant women is a challenge of all times. As a developing organism, the fetus is particularly vulnerable to effects of drugs used by the mother. Historically, research has predominantly focused on birth defects, which represent the most studied adverse pregnancy outcomes. However, drugs can also alter the ongoing process of pregnancy and impede the general growth of the fetus. Finally, adverse drug reactions can theoretically damage all developing systems, organs or tissues, such as the central nervous system or the immune system. This extensive review focuses on different aspects of drug-induced damages affecting the fetus or the newborn/infant, beyond birth defects, which are not addressed here., (Copyright © 2023 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Background: A major breakthrough in cystic fibrosis (CF) therapy was achievedAQ1 with CFTR modulators. The lumacaftor/ivacaftor combination is indicated for the treatment of CF in pediatric patients above 6 years old. Pharmacokinetic (PK) studies of lumacaftor/ivacaftor in these vulnerable pediatric populations are AQ2crucial to optimize treatment protocols., Objectives and Methods: The objectives of this study were to describe the population PK (PPK) of lumacaftor and ivacaftor in children with CF, and to identify factors associated with interindividual variability. The association between drug exposure and clinical response was also investigated., Results: A total of 75 children were included in this PPK study, with 191 concentrations available for each compound and known metabolites (lumacaftor, ivacaftor, ivacaftor-M1, and ivacaftor-M6). PPK analysis was performed using Monolix software. A large interindividual variability was observed. The main sources of interpatient variability identified were patient bodyweight and hepatic function (aspartate aminotransferase). Forced expiratory volume in the first second (FEV1) was statistically associated with the level of exposure to ivacaftor after 48 weeks of treatment., Conclusions: This study is the first analysis of lumacaftor/ivacaftor PPK in children with CF. These data suggest that dose adjustment is required after identifying variability factors to optimize efficacy. The use of therapeutic drug monitoring as a basis for dose adjustment in children with CF may be useful., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: Describe the trends of exposure to harmful drugs during pregnancy over recent years in France., Design: Nationwide cohort study., Setting: The French National administrative health Data System (SNDS)., Population: Pregnancies starting between 2013 and 2019 and outcomes corresponding to live births, medical terminations of pregnancy, and stillbirths., Methods: Each pregnancy was divided into a preconceptional period of 90 days before conception and three trimesters from conception to birth. Harmful drugs were defined according to their risks to the fetus: teratogenicity or fetotoxicity. Exposure was defined using the critical period during pregnancy for each type of harmful drug: preconceptional period or first trimester for teratogenic drugs and second or third trimesters for fetotoxic drugs., Main Outcome Measures: Prevalence of pregnancies exposed to at least one harmful drug., Results: Among 5,253,284 pregnancies, 204,402 (389 per 10,000) pregnancies were exposed to at least one harmful drug during the critical periods: 48,326 (92 per 10,000) pregnancies were exposed to teratogenic drugs during the preconceptional period or the first trimester, and 155,514 (299 per 10,000) pregnancies were exposed to fetotoxic drugs during the second or third trimesters. Teratogenic drugs were mainly retinoids for topical use (44 per 10,000 pregnancies), antiepileptics (13 per 10,000 pregnancies) and statins (13 per 10,000 pregnancies). Fetotoxic drugs were mainly non-steroidal anti-inflammatory drugs (NSAIDs), for systemic (128 per 10,000 pregnancies) and topical use (122 per 10,000 pregnancies). Exposure to teratogenic drugs decreased from the preconceptional period to the first trimester. Exposure to fetotoxic drugs decreased from the second to the third trimester. Between 2013 and 2019, we found a decrease in harmful drug exposure overall, mainly for topical and systemic NSAIDs and for topical retinoids., Conclusions: In this nationwide study, about one in 25 pregnancies was exposed to at least one harmful drug, mainly NSAIDs and topical retinoids. Although the prevalence of harmful drug exposure decreased over the study period, NSAID exposure in the second and third trimester remains of concern., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Louchet et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Patent ductus arteriosus (PDA) in preterm infants is associated with increased morbidities and mortality. Prophylactic treatment with cyclooxygenase inhibitors, as indomethacin or ibuprofen, failed to demonstrate significant clinical benefits. Acetaminophen may represent an alternative treatment option., Objective: This study evaluated the minimum effective dose of prophylactic acetaminophen to close the ductus and assessed the safety and tolerability profile in extremely preterm infants at 23-26 weeks of gestation., Methods: A dose finding trial with Bayesian continual reassessment method was performed in a multicenter study with premature infants hospitalized in neonatal intensive care unit. Infants of 23-26 weeks of gestation and post-natal age ≤ 12 h were enrolled. Four intravenous acetaminophen dose levels were predefined. The primary outcome was the ductus arteriosus closing at two consecutive echocardiographies or at day 7. The main secondary objectives included the safety of acetaminophen on hemodynamics and biological hepatic function., Results: A total of 29 patients were analyzed sequentially for the primary analysis with 20 infants assigned to the first dose level followed by 9 infants to the second dose level. No further dose level increase was necessary. The posterior probabilities of success, estimated from the Bayesian logistic model, were 46.1% [95% probability interval (PI), 24.9-63.9] and 67.6% (95% PI, 51.5-77.9) for dose level 1 and 2, respectively. A closing or closed pattern was observed among 19 patients at the end of treatment [65.5% (95% confidence interval (CI), 45.7-82.0)]. No change in alanine aminotransferase values was observed during treatment. A significant decrease in aspartate aminotransferase values was observed with postnatal age. No change in systolic and diastolic blood pressures was observed during treatment., Conclusions: Minimum effective dose to close the ductus was 25 mg/kg loading dose then 10 mg/kg/6 h for 5 days in extremely preterm infants. Acetaminophen was well tolerated in this study following these doses., Trial Registration: ClinicalTrials.gov Identifier: NCT04459117., (© 2023. The Author(s).)

Although anti-severe acute respiratory syndrome-coronavirus 2 antibody kinetics have been described in large populations of vaccinated individuals, we still poorly understand how they evolve during a natural infection and how this impacts viral clearance. For that purpose, we analyzed the kinetics of both viral load and neutralizing antibody levels in a prospective cohort of individuals during acute infection with alpha variant. Using a mathematical model, we show that the progressive increase in neutralizing antibodies leads to a shortening of the half-life of both infected cells and infectious viral particles. We estimated that the neutralizing activity reached 90% of its maximal level within 11 days after symptom onset and could reduce the half-life of both infected cells and circulating virus by a 6-fold factor, thus playing a key role to achieve rapid viral clearance. Using this model, we conducted a simulation study to predict in a more general context the protection conferred by pre-existing neutralization titers, due to either vaccination or prior infection. We predicted that a neutralizing activity, as measured by 50% effective dose > 10 3 , could reduce by 46% the risk of having viral load detectable by standard polymerase chain reaction assays and by 98% the risk of having viral load above the threshold of infectiousness. Our model shows that neutralizing activity could be used to define correlates of protection against infection and transmission., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Immunotherapy (IT) is a major therapeutic strategy for lymphoma, significantly improving patient prognosis. IT remains ineffective for a significant number of patients, however, and exposes them to specific toxicities. The identification predictive factors around efficacy and toxicity would allow better targeting of patients with a higher ratio of benefit to risk. PRONOSTIM is a multicenter and retrospective study using the Clinical Data Warehouse (CDW) of the Greater Paris University Hospitals network. Adult patients with Hodgkin lymphoma or diffuse large-cell B lymphoma treated with immune checkpoint inhibitors or CAR T (Chimeric antigen receptor T) cells between 2017 and 2022 were included. Analysis of covariates influencing progression-free survival (PFS) or the occurrence of grade ≥3 toxicity was performed. In total, 249 patients were included. From this study, already known predictors for response or toxicity of CAR T cells such as age, elevated lactate dehydrogenase, and elevated C-Reactive Protein at the time of infusion were confirmed. In addition, male gender, low hemoglobin, and hypo- or hyperkalemia were demonstrated to be potential predictive factors for progression after CAR T cell therapy. These findings prove the attractiveness of CDW in generating real-world data, and show its essential contribution to identifying new predictors for decision support before starting IT.

Objectives: Concerns have been raised regarding neuropsychiatric adverse drug reactions of integrase inhibitors (INSTIs) in patients living with HIV. The aim of this study was to assess the risk of depression and suicidality reporting with INSTIs based on a global pharmacovigilance database., Methods: Depression and suicidality cases in patients treated with INSTIs were identified within the WHO global database of individual case safety reports, VigiBase. Risk of depression and suicidality reporting with INSTIs compared with other ART was assessed using disproportionality analyses (case/non-case statistical approach)., Results: Of 19 991 410 reports over the study period, 124 184 reports concerned patients exposed to ART, including 22 661 patients exposed to an INSTI. Among patients treated with an INSTI, 547 cases of depression and 357 cases of suicidality were identified. Disproportionality analyses showed that depression [reporting OR (ROR) 3.6; 95% CI: 3.2-4.0] and suicidality (ROR 4.7; 95% CI: 4.1-5.4) were more reported with the use of INSTIs compared with other ART. Amongst INSTIs, depression reporting was significantly greater for bictegravir and dolutegravir, whereas suicidality reporting was significantly greater for dolutegravir only., Conclusions: Our findings suggest that depression and suicidality are adverse drug reactions of all INSTI agents, especially dolutegravir, which may occur within the first months of therapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Competing Interests: The authors declare no conflict of interest.

Purpose: To characterize clinical profile of pediatric local anesthetic (LA) systemic toxicity (LAST) and to identify determinants of life-threatening outcomes., Methods: Spontaneous reports notified to the French Pharmacovigilance Network were retrieved and followed by a case-by-case review, according to the following criteria: LA as suspected drug, age < 18 years, adverse drug reactions related to nervous system, cardiac, respiratory, psychiatric or general disorders. Multivariate logistic regression analysis was performed to identify factors leading to life-threatening reaction (i.e. continuous seizures or cardiorespiratory arrest)., Results: Among 512 cases retrieved, 64 LAST cases were included (neonates 11%, infants 30%, children 36%, adolescents 23%) mainly involving lidocaine (47%), lidocaine + prilocaine (22%) and ropivacaine (14%). Toxicity profiles were neurological (58%), cardiac (11%) or mixed (20%) and 7 patients (11%) developed methemoglobinemia. LAST was life-threatening for 23 patients (36%) and 2 patients died. Doses were above recommendations in 26 patients (41%) and were not different between life-threatening and non-life-threatening cases. The context of use (general and orthopedic surgery, p = 0.006) and the type of LA agent (lidocaine, p = 0.016) were independently associated with a life-threatening outcome., Conclusion: In this national retrospective analysis, LAST in children appear to be a rare event. Neurological and cardiac signs were the most frequently reported reactions. LAST in children can be life-threatening, even at therapeutic doses. Although a fatal outcome may anecdotally occur, the vast majority of patients recovered after appropriate medical care., (© 2023. The Author(s).)

Less than one-quarter of oral health trials are registered in a public registry. However, no study has assessed the extent of study publication and selective outcome reporting bias in the field of oral health. We identified oral health trials registered between 2006 and 2016 in ClinicalTrials.gov. We assessed whether results of early discontinued trials, trials having an unknown status, and completed trials had been published and, among published trials, whether outcomes differed between the registered record and the corresponding publication. We included 1,399 trials, of which 81 (5.8%) were discontinued, 247 (17.7%) had an unknown status, and 1,071 (76.6%) were completed. The registration was prospective for 719 (51.9%) trials. Over half the registered trials were unpublished ( n  = 793, 56.7%). To explore the association between trials publication and characteristics of trials, we performed a multivariate logistic regression analysis. Trials conducted in the United States ( P  = 0.003) or Brazil ( P  < 0.001) were associated with increased odds of publication, whereas trials registered prospectively ( P  = 0.001) and industry-sponsored trials ( P  = 0.02) were associated with decreased odds. Among the 479 published trials with completed status, the primary outcomes of 215 (44.9%) articles differed from that registered. Major discrepancies consisted of the introduction of a new primary outcome in the published article (196 [91.2%]) and the transformation of a registered secondary outcome into a primary outcome (112 [52.1%]). In the remaining 264 (55.1%) trials, primary outcomes did not differ from that registered, but 141 (53.4%) had been registered retrospectively. Our study highlights the high rate of nonpublication and selective outcome reporting in the field of oral health. These results could alert sponsors, funders, authors of systematic reviews, and the oral health research community at large to combat the nondisclosure of trial results.

Objectives: Cytomegalovirus (CMV) is the leading cause of congenital infection worldwide. Reference anti-CMV treatment is valganciclovir/ganciclovir, which is contraindicated in pregnancy given questions about teratogenicity., Methods: We analysed reports from VigiBase, the world's largest safety database, and performed a disproportionality analysis of adverse pregnancy outcomes associated with (val)ganciclovir compared with any other drugs or with (val)aciclovir as comparators., Results: Among 3 104 984 reports related to childbearing-age women or to pregnancy topics, 6186 were exposed to (val)ganciclovir or (val)aciclovir including 251 adverse pregnancy outcomes with (val)ganciclovir (n = 34) or (val)aciclovir (n = 217). We did not evidence any increased reporting of any adverse pregnancy outcome [miscarriage, stillbirth, small weight for gestational age, preterm birth (<37 weeks of gestation)] or birth defects with (val)ganciclovir compared with the use of (val)aciclovir during pregnancy. Four cases of oesophageal and anorectal atresia were identified with (val)ganciclovir, which may be related to concomitant drugs/medical conditions and require further analyses., Conclusions: These preliminary results require confirmation but suggest the possibility for trial evaluation of val(ganciclovir) in severe maternal or fetal CMV infections., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The phosphatidylinositol 3-kinase (PI3K) pathway plays a key role in cancer progression and in host immunity. Idelalisib was the first of this class to be approved with the second-generation Pi3 kinase inhibitors copanlisib, duvelisib and umbralisib, subsequently being approved in the United States. Real-world data are lacking, however, in relation to the incidence and toxicity of Pi3 kinase inhibitor-induced colitis. We here review, in the first instance, the general landscape of the Pi3K inhibitors in the context of hematological malignancies, with a focus on the adverse gastrointestinal side effects reported by various clinical trials. We further review the available worldwide pharmacovigilance data in relation to these drugs. Finally, we describe our own real-world experience with idelalisib-induced colitis management in our center and in a national setting.

Purpose: Out-of-hospital cardiac arrest (OHCA) has a poor prognosis, with an overall survival rate of about 5% at discharge. Shockable rhythm cardiac arrests (ventricular fibrillation (VF) and pulseless ventricular tachycardia (VT)) have a better prognosis. In case of shockable rhythm, treatment is based on defibrillation, and thereafter, in case of failure of 3 external electric shocks (EES), on direct intravenous administration of 300 mg amiodarone, or lidocaine when amiodarone is unavailable or inefficient. During surgical procedures under extracorporeal circulation, a high potassium cardioplegia solution is administered to interrupt cardiac activity and facilitate surgical procedure. By extension, direct intravenous administration of potassium chloride (KCl) has been shown to convert VF, resulting in return to a hemodynamically efficient organized heart rate within a few minutes. The aim of this study is to provide clinical evidence that direct intravenous injection of KCl, into a patient presenting with OHCA due to refractory VF although 3 EES, should interrupt this VF and then allow rapid restauration of an organized heart rhythm, and thus return of spontaneous circulation (ROSC)., Methods: A multicenter, prospective, single group, phase 2 study will be conducted on 81 patients presenting with refractory VF. After failure of 3 EES, each patient will receive direct intravenous injection of 20 mmol KCl instead of amiodarone. The primary outcome will be survival rate at hospital admission. Major secondary outcomes will include ROSC and time to ROSC in the prehospital setting, number of VF recidivism after KCl injection, survival rate at hospital discharge with a good neurologic prognostic, and survival rate 3 months after hospital discharge with a good neurologic prognostic., Results: No patient is currently included in the study., Discussion: Conventional guideline strategy based on antiarrhythmic drug administration, i.e. amiodarone or lidocaine, for OHCA due to shockable rhythm, has not yet demonstrated an increase in survival at hospital admission or at hospital discharge. This may be related to the major cardiodepressant effect of those drugs., Trial Registration: ClinicalTrials.gov Identifier: NCT04316611. Registered on March 2020. AP-HP180577 / N° EUDRACT: 2019-002544-24. Funded by the French Health Ministry. https://clinicaltrials.gov/ct2/show/NCT04316611., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Jouffroy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Despite various international regulatory initiatives over the last 20 years, many challenges remain in the field of paediatric drug development and evaluation. Indeed, drug research and development is still focused essentially on adult indications, thereby excluding many paediatric patients, limiting the feasibility of trials and favouring competing developments. Off-label prescribing persists and the development of age-appropriate dosage forms for children remains limited. Against this background, the members of this panel (TR) recommend the launch of multi-partner exchange forums on specific topics in order to focus new drug research and development on the real, unmet medical needs of children and adolescents, and in keeping with the underlying mechanisms of action. Scientific information sharing and cooperation between stakeholders are also essential for defining reference evaluation methods in each medical field. These forums can be organised through existing paediatric facilities and research networks at the French and European level. The latter are specifically dedicated to paediatric research and can facilitate clinical trial implementation and patient enrolment. Moreover, specific grants and public/private partnerships are still needed to support studies on the repositioning of drugs in paediatric indications, and pharmacokinetic studies aimed at defining appropriate dosages. The development of new pharmaceutical forms, better suited for paediatric use, and the promotion of resulting innovations will stimulate future investments. Initiatives to gather observational safety and efficacy data following off-label and/or derogatory early access should also be encouraged to compensate for the lack of information available in these situations. Finally, the creation of Ethics Committees (EC) with a specific "mother-child" advisory expertise should be promoted to ensure that the current regulation (Jardé law in France) is implemented whilst also taking into account the paediatric specificities in medical trials., (Copyright © 2022. Published by Elsevier Masson SAS.)

Introduction: While antipsychotic-induced weight gain has been widely described in adults, it has yet to be better characterized in children and adolescents., Objective: The aim of this study was to assess antipsychotic-induced weight-gain reporting in children and adolescents as compared to adults, and according to the type of antipsychotic., Methods: The study is an observational, case-non-case study using individual case safety reports from the WHO global pharmacovigilance database VigiBase ® from 1 January 2000 to 2 June 2021. Disproportionality in antipsychotic-related weight-gain reporting in children and adolescents compared to adults was evaluated based on reporting odds ratios (RORs) with corresponding 95% confidence intervals (CIs) through multivariate logistic regression modeling. Analysis was adjusted for sex, region of reporting, year of notification, reporter qualification, concomitant use of antidepressants, and use of more than one antipsychotic., Results: Among 282,224 antipsychotic-related spontaneous reports included in this analysis, we identified 16,881 (6.0%) weight-gain cases. Disproportionality in weight-gain reporting was found in children (adjusted ROR (aROR) 3.6; 95% CI 3.3-3.8) and in adolescents (aROR 2.3; 95% CI 2.2-2.4) compared to adults. Use of risperidone was associated with the highest increase in weight-gain reporting in children (aROR 4.9; 95% CI 3.9-6.1) and adolescents (aROR 3.6; 95% CI 3.1-4.1)., Conclusions: Compared to adults, weight-gain reporting with antipsychotics was disproportionally higher in the pediatric population, especially in children under 12 years of age. Considering the impact of weight gain on global morbidity and mortality, physicians should closely monitor weight gain in young patients, especially children on risperidone., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: RTX is used off-label in several neurological inflammatory diseases in adults children patients. We conducted a study to assess indications and safety of rituximab (RTX) for children and to identify risk factors for early B-cell repopulation., Methods: A single-center retrospective study of children treated with RTX for a neurological disease between May 31, 2010, and May 31, 2020, was performed., Results: A total of 77 children (median age, 8.9 years) were included. RTX was mostly used as second-line therapy in all groups of diseases (68%). Median dose was 1500 mg/m 2 for each patient. There were 13 clinical relapses (17%), 5 when B-cell depletion was complete. Adverse events were present in 6% of the cases. The factors influencing early B-cell repopulation were the recent infusion of intravenous Ig (P < 0.01) and the administration of less than 1500 mg/m 2 during the first RTX treatment (P = 0.04). The median time to B-cell repopulation seemed to be shorter (160 vs 186 days) when patients had plasmapheresis even when a 48-hour delay was observed with RTX infusions., Conclusions: This study confirms the good tolerance of RTX in the treatment of specific neurological disorders in a pediatric population. It also highlights risk factors for early B-cell repopulation and underlines the importance of B-cell monitoring., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The population pharmacokinetics of amiodarone and its active metabolite, N-desethylamiodarone (DEA) were investigated in paediatric patients with arrhythmias, mainly supraventricular tachycardias. A total of 55 patients from the Department of Pediatric Intensive Care and Pediatric Cardiology at Necker-Enfants malades Hospital (Paris, France) provided 72 concentrations for both amiodarone and DEA following repeated oral or intravenous administration. Blood samples drawn for biological analyses were used for drug concentrations. Plasma amiodarone concentrations were measured by a liquid chromatography method coupled with mass spectrometry and the data were modelled using the software Monolix 2019R2. Parent pharmacokinetics was described with a 2-compartment open model and the metabolite formation was connected to the central parent compartment. Parameter estimates scaled allometrically on bodyweight (normalized to 70 kg) were, respectively (% relative standard errors, RSEs), 6.32 (31%) and 7.14 L/h (26%) for elimination (CL) and intercompartmental clearances and 167 (31%) and 3930 (32%) L for V 1 and V 2 . Oral bioavailability was 0.362 (21.5%). The clearance between subject variability (ω, square root of the variance) was 0.462 (RSE 21%). The proportional residual variabilities were respectively 0.453 (RSE 13%) and 0.423 (RSE 12%) for amiodarone and DEA respectively. The terminal half-lives were 34 and 14.5 days for amiodarone and DEA, respectively. A dosage schedule was established for 3 weight bands in 2 time periods. The high pharmacokinetic variability suggests that therapeutic drug monitoring might be useful to improve individual efficacy and safety., (© 2022 British Pharmacological Society.)

Several cases of herpes zoster (HZ) following mRNA COVID-19 vaccination (BNT162b2 and mRNA-1273) have been reported, and the first epidemiological evidence suggests an increased risk. We used the worldwide pharmacovigilance database VigiBase to describe HZ cases following mRNA COVID-19 vaccination. We performed disproportionality analyses (case/non-case statistical approach) to assess the relative risk of HZ reporting in mRNA COVID-19 vaccine recipients compared to influenza vaccine recipients and according to patient age. To 30 June 2021, of 716 928 reports with mRNA COVID-19 vaccines, we found 7728 HZ cases. When compared to influenza vaccines, mRNA COVID-19 vaccines were associated with a significantly higher reporting of HZ (reporting odds ratio 1.9, 95% CI 1.8-2.1). Furthermore, we found a reduced risk of reporting HZ among under 40-year-old persons compared to older persons (reporting odds ratio 0.39, 95% CI 0.36-0.41). Mild and infrequent HZ reactions may occur shortly after mRNA COVID-19 vaccination, at higher frequency than reported with influenza vaccination, especially in patients over 40 years old. Further analyses are needed to confirm this risk., (© 2022 British Pharmacological Society.)

Competing Interests: Conflicts of interest None disclosed.

Background: Throughout the COVID-19 pandemic, testing individuals remains a key action. One approach to rapid testing is to consider the olfactory capacities of trained detection dogs., Methods: Prospective cohort study in two community COVID-19 screening centers. Two nasopharyngeal swabs (NPS), one saliva and one sweat samples were simultaneously collected. The dog handlers (and the dogs…) were blinded with regards to the Covid status. The diagnostic accuracy of non-invasive detection of SARS-CoV-2 infection by canine olfaction was assessed as compared to nasopharyngeal RT-PCR as the reference standard, saliva RT-PCR and nasopharyngeal antigen testing., Results: 335 ambulatory adults (143 symptomatic and 192 asymptomatic) were included. Overall, 109/335 participants tested positive on nasopharyngeal RT-PCR either in symptomatic (78/143) or in asymptomatic participants (31/192). The overall sensitivity of canine detection was 97% (95% CI, 92 to 99) and even reached 100% (95% CI, 89 to 100) in asymptomatic individuals compared to NPS RT-PCR. The specificity was 91% (95% CI, 72 to 91), reaching 94% (95% CI, 90 to 97) for asymptomatic individuals. The sensitivity of canine detection was higher than that of nasopharyngeal antigen testing (97% CI: 91 to 99 versus 84% CI: 74 to 90, p = 0.006), but the specificity was lower (90% CI: 84 to 95 versus 97% CI: 93 to 99, p = 0.016)., Conclusions: Non-invasive detection of SARS-CoV-2 infection by canine olfaction could be one alternative to NPS RT-PCR when it is necessary to obtain a result very quickly according to the same indications as antigenic tests in the context of mass screening., Competing Interests: The authors have declared that no competing interests exist.

Purpose: The role of angiotensin receptor blockers (ARB), angiotensin-converting enzyme inhibitors (ACEi), or other antihypertensive agents in the case of Covid-19 remains controversial. We aimed to investigate the association between antihypertensive agent exposure and in-hospital mortality in patients with Covid-19., Methods: We performed a retrospective multicenter cohort study on patients hospitalized between February 1 and May 15, 2020. All patients had been followed up for at least 30 days., Results: Of the 8078 hospitalized patients for Covid-19, 3686 (45.6%) had hypertension and were included in the study. In this population, the median age was 75.4 (IQR, 21.5) years and 57.1% were male. Overall in-hospital 30-day mortality was 23.1%. The main antihypertensive pharmacological classes used were calcium channel blockers (CCB) (n=1624, 44.1%), beta-blockers (n=1389, 37.7%), ARB (n=1154, 31.3%), and ACEi (n=998, 27.1%). The risk of mortality was lower in CCB (aOR, 0.83 [0.70-0.99]) and beta-blockers (aOR, 0.80 [0.67-0.95]) users and non-significant in ARB (aOR, 0.88 [0.72-1.06]) and ACEi (aOR, 0.83 [0.68-1.02]) users, compared to non-users. These results remain consistent for patients receiving CCB, beta-blocker, or ARB as monotherapies., Conclusion: This large multicenter retrospective of Covid-19 patients with hypertension found a reduced mortality among CCB and beta-blockers users, suggesting a putative protective effect. Our findings did not show any association between the use of renin-angiotensin-aldosterone system inhibitors and the risk of in-hospital death. Although they need to be confirmed in further studies, these results support the continuation of antihypertensive agents in patients with Covid-19, in line with the current guidelines., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: This study aimed at characterizing the pharmacokinetics (PK) of oral levofloxacin in adult patients in order to optimize dosing scheme and explore the PK/pharmacodynamics (PD) of levofloxacin in bone and joint infections (BJIs)., Methods: From November 2015 to December 2019, all patients hospitalized in Cochin Hospital, treated with levofloxacin and who had at least one dosage for therapeutic drug monitoring were included. PK was described using non-linear mixed-effect modelling. In a subgroup of patients with BJIs, the association between PK, MIC for the isolated pathogen and clinical outcome was investigated. Monte Carlo simulations investigated dosing regimens to achieve the PK/PD target (AUC/MIC ratio >100)., Results: One hundred and two patients were included (199 measurements), including 32 treated for BJI. A one-compartment model with first-order absorption and elimination best described the data. Effects of estimated creatinine clearance (eCLCR) and age were significant on levofloxacin clearance. In BJI patients, no significant association was found between levofloxacin PK/microbiological parameters and either clinical outcome or adverse events. Based on our model, we proposed optimized oral levofloxacin dosing regimens according to renal function, to reach the PK/PD target AUC/MIC ratio >100 for three frequent causative pathogens (Staphylococcus aureus, Enterobacterales and Pseudomonas aeruginosa)., Conclusions: Our results reinforce the need of determining the MIC and using therapeutic drug monitoring in complex infections caused by P. aeruginosa., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In response to the World Health Organization call for research on alternative routes for tranexamic acid (TXA) administration in women with postpartum haemorrhage, we examined the pharmacokinetics of TXA after i.v., i.m., or oral administration., Methods: We conducted a randomised, open-label, crossover trial in 15 healthy volunteers who received i.v. TXA 1 g, i.m. TXA 1 g, or oral TXA solution 2 g. Blood samples were drawn up to 24 h after administration. Tranexamic acid concentration was measured with liquid chromatography-mass spectrometry, and the parameters of the pharmacokinetic models were estimated using population pharmacokinetics., Results: The median time to reach a concentration of 10 mg L -1 was 3.5 min for the i.m. route and 66 min for the oral route, although with the oral route the target concentration was reached in only 11 patients. Median peak concentrations were 57.5, 34.4, and 12.8 mg L -1 for i.v., i.m., and oral routes, respectively. A two-compartment open model with body weight as the main covariate best fitted the data. For a 70 kg volunteer, the population estimates were 10.1 L h -1 for elimination clearance, 15.6 L h -1 for intercompartmental clearance, 7.7 L for the volume of central compartment, and 10.8 L for the volume of the peripheral compartment. Intramuscular and oral bioavailabilities were 1.0 and 0.47, respectively, showing that i.m. absorption is fast and complete. Adverse events were mild and transient, mainly local reactions and low-intensity pain., Conclusions: The i.m. (but not oral) route appears to be an efficient alternative to i.v. tranexamic acid. Studies in pregnant women are needed to examine the impact of pregnancy on the pharmacokinetics., Clinical Trial Registration: EudraCT 2019-000285-38; NCT03777488., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Myocarditis and pericarditis may constitute adverse reactions of mRNA coronavirus disease 2019 (COVID-19) vaccines. This study aimed to document these reactions and to assess the association with patient sex and age. This is as an observational retrospective study using a case-non-case design (also called disproportionality study) on inflammatory heart reactions reported with mRNA COVID-19 vaccines within the World Health Organization (WHO) global safety database (VigiBase), up to June 30, 2021. Results are expressed using reporting odds ratios (RORs) and their 95% confidence interval (95% CI). Of 716,576 reports related to mRNA COVID-19 vaccines, 2,277 were cases of inflammatory heart reactions, including 1241 (55%) myocarditis and 851 (37%) pericarditis. The main age group was 18-29 years (704, 31%), and mostly male patients (1,555, 68%). Pericarditis onset was delayed compared with myocarditis with a median time to onset of 8 (3-21) vs. 3 (2-6) days, respectively (P = 0.001). Regarding myocarditis, an important disproportionate reporting was observed in adolescents (ROR, 22.3, 95% CI 19.2-25.9) and in 18-29 years old (ROR, 6.6, 95% CI 5.9-7.5) compared with older patients, as well as in male patients (ROR, 9.4, 95% CI 8.3-10.6). Reporting rate of myocarditis was increased in young adults and adolescents. Inflammatory heart reactions may rarely occur shortly following mRNA COVID-19 vaccination. Although an important disproportionate reporting of myocarditis was observed among adolescents and young adults, particularly in male patients, reporting rates support a very rare risk, that does not seem to compromise the largely positive benefit-risk balance of these vaccines. Furthermore, this study confirmed the value of disproportionality analyses for estimation of relative risks among subgroups of patients., (© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Severe combined immunodeficiencies (SCIDs) correspond to the most severe form of primary immunodeficiency. Allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy are curative treatments, depending on the donor's availability and molecular diagnostics. A partially human leukocyte antigen (HLA)-compatible donor used has been developed for this specific HSCT indication in the absence of a matched donor. However, the CD34+ selected process induces prolonged post-transplant T-cell immunodeficiency. The aim here was to investigate a modeling approach to predict the time course and the extent of CD4+ T-cell immune reconstitution after CD34+ selected transplantation. We performed a Bayesian approach based on the age-related changes in thymic output and the cell proliferation/loss model. For that purpose, we defined specific individual covariates from the data collected from 10 years of clinical practice and then evaluated the model's predicted performances and accuracy. We have shown that this Bayesian modeling approach predicted the time course and extent of CD4+ T-cell immune reconstitution after SCID transplantation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The Reviewer SP has declared a past collaboration with several of the authors DM and BN to the handling editor., (Copyright © 2022 Diana, Bouazza, Couzin, Castelle, Magnani, Magrin, Rosain, Treluyer, Picard, Moshous, Blanche, Neven and Cavazzana.)

We assessed the accuracy of tranexamic acid (TXA) concentrations measured in capillary whole blood using volumetric absorptive micro-sampling (VAMS) devices. Paired venous and VAMS capillary blood samples were collected from 15 healthy volunteers participating in a pharmacokinetic study of alternative routes (oral, IM and IV) of administering TXA. To assess accuracy across a range of concentrations, blood was drawn at different times after TXA administration. We measured TXA concentrations in plasma, whole blood from samples collected by venepuncture and whole blood from venous and capillary samples collected using VAMS devices. TXA was measured using a validated high sensitivity liquid chromatography - mass spectrometry method. We used Bland-Altman plots to describe the agreement between the TXA concentrations obtained with the different methods. In the 42 matched samples, the mean plasma TXA concentration was 14.0 mg/L (range 2.6-36.5 mg/L) whereas the corresponding whole blood TXA concentration was 7.7 mg/L (range 1.6-17.5 mg/L). When comparing TXA concentrations in VAMS samples of venous and capillary whole blood, the average bias was 0.07 mg/L (lower and upper 95% limits of agreement: -2.1 and 2.2 mg/L respectively). When comparing TXA concentrations in venous whole blood and VAMS capillary whole blood, the average bias was 0.7 mg/L (limits of agreement: -2.7 and 4.0 mg/L). Volumetric absorptive micro-sampling devices are sufficiently accurate for use in pharmacokinetic studies of tranexamic acid treatment in the range of plasma concentrations relevant for the assessment of fibrinolysis inhibition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Grassin-Delyle, Lamy, Semeraro, Runge, Treluyer, Mansukhani, Arribas, Roberts and Shakur-Still.)

Synthetized by the liver and metabolized by the gut microbiota, BA are involved in metabolic liver diseases that are associated with cardiovascular disorders. Animal models of atheroma documented a powerful anti-atherosclerotic effect of bile acids (BA). This prospective study examined whether variations in circulating BA are predictive of coronary artery disease (CAD) in human. Consecutive patients undergoing coronary angiography were enrolled. Circulating and fecal BA were measured by high pressure liquid chromatography and tandem mass spectrometry. Of 406 screened patients, 80 were prospectively included and divided in two groups with (n = 45) and without (n = 35) CAD. The mean serum concentration of total BA was twice lower in patients with, versus without CAD (P = 0.005). Adjusted for gender and age, this decrease was an independent predictor of CAD. In a subgroup of 17 patients, statin therapy doubled the serum BA concentration. Decreased serum concentrations of BA were predictors of CAD in humans. A subgroup analysis showed a possible correction by statins. With respect to the anti-atherosclerotic effect of BA in animal models, and their role in human lipid metabolism, this study describe a new metabolic disturbance associated to CAD in human., (© 2021. The Author(s).)