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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. [ABSTRACT FROM AUTHOR]

Aim: According to experimental studies, cardiopulmonary distress decreases after closure of patent ductus arteriosus. However, early closure of the ductus using ibuprofen or indomethacin has failed to increase survival without serious morbidity. We review relevant data aiming to define optimal early management strategies that promote early closure of ductus arteriosus without serious adverse effects. Methods: Literature in English was searched selectively focusing on the potential of using acetaminophen for early closure of the ductus. Results: Prophylactic ibuprofen or indomethacin intended to close the ductus, predisposes infants to ischaemia, bleeding and immune dysfunction. Acetaminophen appears to have a similar efficacy as indomethacin or ibuprofen, and all three dose‐dependently constrict the ductus. Ibuprofen and indomethacin cause non‐specific inhibition of prostaglandin synthesis, while acetaminophen predominantly inhibits prostaglandin E synthesis. Owing to low CYP450 activity in infancy, acetaminophen toxicity has been rarely evident. However, increasing the dosage increases the oxidative stress. We review prophylactic treatments that may increase the safety and efficacy of acetaminophen. These include vitamin A, cysteine and glutamine, and low‐dose corticosteroid supplementation. Conclusion: The current challenge is to define a safe perinatal management practice that promotes cardiorespiratory adaptation in immature infants, particularly the seamless closure of the ductus before significant cardiopulmonary distress develops. [ABSTRACT FROM AUTHOR]

Background: Among adolescents with type 1 diabetes, some experience great difficulties with treatment adherence, putting them at high risk of complications. We assessed the effect of text messaging (Short Messaging Service [SMS]) on glycemic control. Methods: A two-arm open label randomized controlled trial enrolled adolescents with type 1 diabetes aged 12–21 years with baseline HbA1c ≥ 69 mmol/mol (8.5%). The intervention group received daily SMS reminders at self-selected times about insulin injections while the control group received standard of care. The patients allocated to the control group were not aware of the intervention. Results: 92 patients were randomized, 45 in the SMS arm and 47 in the control arm. After 6 months, median HbA1c level was significantly lower in the intervention arm: 73 mmol/mol (8.8%) in the SMS arm and 83 mmol/mol (9.7%) in the control arm in the intent-to-treat analysis (P = 0.03) but no longer in the per protocol analysis (P = 0.65). When we consider the proportions of patients whose HbA1c level decreased by at least 1% between baseline and 6 months, we find a significant difference among patients whose baseline HbA1c was ≥ 80 mmol/mol (9.5%) (n = 56): 60% in the SMS arm and 30.6% in the control arm had lowered their HbA1c level (P = 0.03) in the intent-to-treat analysis but not in the per-protocol analysis (P = 0.50). Patients in the SMS arm reported high satisfaction with the intervention. Conclusions: While there is a trend to lower HbA1c in the intervention group, no firm conclusions can yet be drawn. Further studies are needed to address methodological issues as we believe these interventions can support behavior change among adolescents with poorly controlled type 1 diabetes. ClinicalTrials.gov identifier: NCT02230137. [ABSTRACT FROM AUTHOR]

Growing evidence suggests that polymorphisms of genes coding for transporters or enzymes may partially explain the large between subject variability reported for methotrexate (MTX) pharmacokinetics (PK). This prospective study aimed to develop a population PK‐pharmacogenetic model to evaluate the part of between‐subject variability due to single‐nucleotide polymorphisms (SNPs) in transporters and enzyme genes implicated in MTX distribution and elimination. MTX concentrations and 54 SNPs (located in ABCB1, ABCC1, ABCC2, ABCC3, ABCC4, ABCG2, SLC19A1, SLCO1B1, and UGT1A1 genes) were analyzed in patients treated with MTX included in the OS2006/sarcoma‐09 trial (a multicenter, open‐label, phase III trial, ClinicalTrials.gov. Identifier: NCT00470223). PK data were analyzed using the nonlinear mixed‐effect modeling software program Monolix. The influence of each SNP was evaluated using a stepwise procedure under additive, recessive, or dominant genetic model. The likelihood ratio test was used to test the effect of each SNP on PK parameters. Overall, 187 patients with 7898 MTX blood concentrations were included in the PK‐pharmacogenetic analysis. A 2‐compartment model adequately described the data. Although high‐dose MTX dosing recommendations in pediatric patients are currently based on body surface area, body weight was more predictive of clearance between‐subject variability than body surface area. The most significant polymorphism associated with MTX clearance was rs13120400 (on the ABCG2 gene) under the recessive genetic model (P <.0001). GG genotype carriers for rs13120400 appeared to have a moderate decrease in MTX exposure compared to AA or GA carriers. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims The main goal of the study was to describe the pharmacokinetics of maternal zidovudine ( ZDV) administration during pregnancy and labour and to evaluate their impact on fetal concentrations and exposures. Methods A total of 195 HIV-infected pregnant and non-pregnant women aged 16-59 years were included and 273 maternal and 79 cord blood ZDV concentrations were collected. A population pharmacokinetic model was developed to describe ZDV concentrations as a function of time in the mother and the fetus. Fetal exposures resulting from maternal oral administration and infusion were estimated and compared with therapeutic exposures (3-5 mg l−1 h) and to exposure providing higher risk of toxicity (>8.4 mg l−1 h). Different protocols for ZDV administration during labour were simulated. Results The median fetal exposure and the percentage of children with values above 8.4 mg l−1 h were 3.20 mg l−1 h and 0% after maternal oral administration, respectively, and 9.71 mg l−1 h and 51% after maternal infusion during labour. Two options were considered to reduce fetal exposure during labour: (i) maternal infusion rates could be 1 mg kg−1 h−1 during 1 h followed by 0.5 mg kg−1 h−1 and (ii) the mother could only take oral ZDV every 5 h from start of labour until delivery with her neonate having their first ZDV dose as soon as possible after birth. Conclusions Zidovudine exposures are very important during labour and during the first days of a neonate's life. Maternal ZDV dose should be reduced in addition to the neonate doses reduction already proposed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

To assess the relationship between genetic polymorphisms and indinavir pharmacokinetic variability and to study the link between concentrations and short-term response or metabolic safety. Forty protease inhibitor-naive patients initiating highly active antiretroviral therapy (HAART) including indinavir/ritonavir and enrolled in the COPHAR 2–ANRS 111 trial were studied. At week 2, four blood samples were taken before and up to 6 h following drug intake. A population pharmacokinetic analysis was performed using the stochastic approximation expectation maximization (SAEM) algorithm implemented in MONOLIX software. The area under the concentration–time curve (AUC) and maximum (Cmax) and trough concentrations (Ctrough) of indinavir were derived from the population model and tested for their correlation with short-term viral response and safety measurements, while for ritonavir, these same three parameters were tested for their correlation with short-term biochemical safety A one-compartment model with first-order absorption and elimination best described both indinavir and ritonavir concentrations. For indinavir, the estimated clearance and volume of distribution were 22.2 L/h and 97.3 L, respectively. The eight patients with the *1B/*1B genotype for the CYP3A4 gene showed a 70% decrease in absorption compared to those with the *1A/*1B or *1A/*1A genotypes (0.5 vs. 2.1, P = 0.04, likelihood ratio test by permutation). The indinavir AUC and Ctrough were positively correlated with the decrease in human immunodeficiency virus RNA between week 0 and week 2 ( r = 0.4, P = 0.03 and r = -0.4, P = 0.03, respectively). Patients with the *1B/*1B genotype also had a significantly lower indinavir Cmax (median 3.6, range 2.1–5.2 ng/mL) than those with the *1A/*1B or *1A/*1A genotypes (median 4.4, range 2.2–8.3 ng/mL) ( P = 0.04) and a lower increase in triglycerides during the first 4 weeks of treatment (median 0.1, range −0.7 to 1.4 vs. median 0.6, range −0.5 to 1.7 mmol/L, respectively; P = 0.02). For ritonavir, the estimated clearance and volume of distribution were 8.3 L/h and 60.7 L, respectively, and concentrations were not found to be correlated to biochemical safety. Indinavir and ritonavir absorption rate constants were found to be correlated, as well as their apparent volumes of distribution and clearances, indicating correlated bioavailability of the two drugs. The CYP3A4*1B polymorphism was found to influence the pharmacokinetics of indinavir and, to some extent, the biochemical safety of indinavir. [ABSTRACT FROM AUTHOR]

The aim of this paper was to describe the time-course of the sedative effect of rectal chloral hydrate (75 mg/kg) in children undergoing CT scan or MRI. Twenty children (2.13 ± 1.43 years old) were administered 75 mg/kg chloral hydrate rectally (chloralhydrat-rectiole rectal formulation, Dr Mann-Pharma Lab, Berlin, Germany), before a CT scan or an NMR imaging. Sedation was measured at specific times using a sedation score of 1–6. Patients were continuously monitored for respiratory and heart rate, systolic and diastolic blood pressures, and oxygen saturation. About 82.35 and 94.11% of the patients had a score of sedation ≥ 3 within 15 and 30 min, respectively. The mean time to effective sedation (score ≥ 3) was of 0.30 ± 0.14 h (median time, 0.25 h). The mean duration of effective sedation (score ≥ 3) was 1.29 ± 1.05 h (median duration, 0.75 h). A total of 93.1% of the X-ray sections were obtained without artifact and sedation was considered by radiologists to be efficient for 83.3% of the procedures. This sedation procedure appeared efficient and safe during ambulatory CT scan and NMR imaging. The long-term effect of chloral hydrate, however, remains to be evaluated. [ABSTRACT FROM AUTHOR]

The CYP2D6 protein is a polymorphic isoenzyme involved in the biotransformation of several drugs including the probe drug dextromethorphan. The rise in the protein concentration, immunochemically determined with a specific antibody, was shown to occur within the first week following birth, whatever the gestational age at birth. In fetuses, the concentration of hepatic CYP2D6 protein was very low or undetectable in 70% of samples tested. In the remaining 30%, its concentration was comparable to that of newborns aged 1–7 days. This early rise was associated with spontaneous abortion in 70% of positive samples, whereas in fetuses with an intermediate CYP2D6 protein concentration, 80% were from induced abortions. The rise in CYP2D6 protein was associated with the developmental onset of dextromethorphan O-demethylation, but not N-demethylation, even if activity was lower in fetal than in neonatal and in adult liver microsomes. Lastly, the CYP2D6 RNA is detectable earlier than the protein and exhibits a peak of hepatic accumulation in newborns, before declining in adulthood. A positive correlation between RNA accumulation and protein concentration can be demonstrated only in the adult. This suggests that regulation is primarily at the transcriptional level, but cannot rule out the participation of post-transcriptional events in the regulation process throughout ontogenesis. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions 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.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.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).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. [ABSTRACT FROM AUTHOR]

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 AUC0–24 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. [ABSTRACT FROM AUTHOR]

The article discusses a study which assessed a potential safety signal for the different types of systemic vasculitis following mRNA COVID-19 vaccination. Topics include association between mRNA COVID-19 vaccines and increased reporting in Behcet's syndrome, factors that are likely to play a role in the onset of systemic vasculitis, and the use World Health Organization (WHO) global safety database to assess potential safety signals for the different types of systemic vasculitis.

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. [ABSTRACT FROM AUTHOR]

The article discusses a study that examined the potential use of drug candidate, favipiravir in treating children with Ebola in west Africa. Topics discussed include the percentage of children in the infected with Ebola virus from the outbreak in Guinea and proposed dosage regimen in a trial in Guinea assessing survival in children with Ebola ad treated with favipiravir.

Supplemental Digital Content is Available in the Text. Background: Dolutegravir, an integrase strand transfer inhibitor (InSTI), is a major antiretroviral agent for HIV infection. Its use is promising, especially in low- and middle-income countries, because of a high resistance barrier and a good safety profile. Very recently, a World Health Organization safety signal has been raised regarding neural tube defects after the first-trimester exposure. Furthermore, to date, the experience is limited regarding the use of the other InSTI drugs (raltegravir and elvitegravir) during pregnancy. Our objective is to analyze the safety of InSTI drugs in pregnant women. Setting: Nation-wide database cohort analysis. Methods: We evaluated the risk of major birth defects according to EUROCAT classification in pregnant women, which had had a first-trimester exposure to dolutegravir, raltegravir, or elvitegravir. Results: We found a major birth defect rate of 1.9% in the general population between 2012 and 2016. As InSTI drugs are not used as first-line therapy in pregnant women, we found a very low exposure in this population. Among 49, 240, and 70 pregnancy outcomes exposed to dolutegravir, raltegravir, and elvitegravir, respectively, during the first trimester, there were 2, 3, and 1 major birth defects, respectively. There was no case of neural tube defect. Conclusions: Drug exposure to InSTI is limited in our nation-wide database. Nevertheless, our data do not support a pharmacovigilance signal on neural tube defects in women exposed to dolutegravir, raltegravir or elvitegravir during pregnancy. Owing to a small number of pregnancy outcomes, these results need to be confirmed with further studies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The OPTIPRIM-ANRS 147 trial compared intensive combination ART (darunavir/ritonavir, tenofovir disoproxil fumarate/emtricitabine, raltegravir and maraviroc) started early during primary HIV-1 infection with standard tritherapy with darunavir/ritonavir, tenofovir disoproxil fumarate and emtricitabine. From month 6 to 18, the percentage of viral load values <50 copies/mL was lower in the pentatherapy arm than in the tritherapy arm. Here we compared antiretroviral drug concentrations between the two arms. Methods: Plasma samples were collected from 50 patients at various times after drug administration. A Bayesian approach based on published population pharmacokinetic models was used to estimate residual drug concentrations (Ctrough) and exposures (AUC) in each patient. A mixed linear regression model was then used to compare the AUC and Ctrough values of each drug used in both groups. Results: Published models adequately described our data and could be used to predict CTROUGH and AUC. No significant difference in tenofovir disoproxil fumarate, emtricitabine and ritonavir parameters was found between the two arms. However, darunavir Ctrough and AUC were significantly lower in the pentatherapy arm than in the tritherapy arm (P = 0.03 and P = 0.04, respectively). Conclusions: Adding maraviroc and raltegravir to darunavir-based tritherapy decreased darunavir concentrations. Compliance issues, maraviroc-darunavir interaction and raltegravir-darunavir interaction were suspected and may affect the kinetics of viral decay during pentatherapy. A specific pharmacokinetic interaction study is needed to explore the interactions between darunavir and maraviroc and raltegravir. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy is increasingly used in lymphoma strategy. Risk-adapted therapeutical management and set-up scores to -stratify the most vulnerable patients by risk are becoming major concerns. With the continuing upward trend of real-world data usage in addition to clinical trial data, it is possible to test the feasibility of using data from clinical data warehouses (CDWs) to identify new predictive factors for response or toxicity to immunotherapy. Based on a large set of biological and clinical factors, our results confirm already known predictors factors of CAR T (chimeric antigen receptor T) cells: age, elevated lactate dehydrogenase, and C-Reactive Protein at the time of infusion. Additionally male gender, low hemoglobin, and hypo- or hyperkalemia are demonstrated to be predictive factors for progression after CAR T cell therapy. Thus, the attractiveness of CDW for generating data by building ever larger cohorts is proven, enabling significant results to be obtained in line with those previously described in the literature. 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. [ABSTRACT FROM AUTHOR]

About 15% to 28% of patients treated with thiopurines experienced adverse drug reactions, such as haematological and hepatic toxicities. Some of these related to the polymorphic activity of the thiopurine S‐methyltransferase (TPMT), the key detoxifying enzyme of thiopurine metabolism. We report here a case of thiopurine‐induced ductopenia with a comprehensive pharmacological analysis on thiopurine metabolism. A 34‐year‐old woman, with a medical history of severe systemic lupus erythematosus with recent introduction of azathioprine therapy, presented with mild fluctuating transaminase blood levels consistent with a hepatocellular pattern, which evolved to a cholestatic pattern over the next weeks. A blood thiopurine metabolite assay revealed low 6‐thioguanine nucleotides (6‐TGN) level and a dramatically increased 6‐methylmercaptopurine ribonucleotides (6‐MMPN) level, together with an unfavourable [6‐MMPN:6‐TGN] metabolite ratio and a high TPMT activity. After a total of about 6 months of thiopurine therapy, a transjugular liver biopsy revealed a ductopenia, and azathioprine discontinuation led to further clinical improvement. In line with previous reports from the literature, our case supports the fact that ductopenia is a rare adverse drug reaction of azathioprine. The mechanism of reaction is unknown but may involve high 6‐MMPN blood level, due to unusual thiopurine metabolism (switched metabolism). Early therapeutic drug monitoring with measurement of 6‐TGN and 6‐MMPN blood levels may help physicians to identify patients at risk of similar duct injury. [ABSTRACT FROM AUTHOR]

Simple Summary: Targeted therapies are becoming more widespread in the treatment of indolent B-cell malignancies, as has been the case for chronic lymphocytic leukemias and small B-cell non-Hodgkin lymphomas. Due to the severity of these diseases, several drugs have received fast track approval since 2014 including the BTK inhibitor ibrutinib, the Bcl2 inhibitor venetoclax and various P13 kinase inhibitors. Of the Pi3 kinase inhibitors, idelalisib was the first of this class to be approved, followed by the second-generation drugs copanlisib, duvelisib and umbralisib. However, the last of these agents have now been withdrawn, partly due to severe gastrointestinal side effects. We herein describe these gastrointestinal effects, as reported in clinical trials, and then review real-world data for these targeted inhibitors using world-wide pharmacovigilance evidence. Our own single-center experience of 15 patients with an indolent B-cell malignancy, from with six biopsies were derived, has helped us to describe the incidence and severity of Pi3 kinase-induced colitis. Histological analysis of these cases yielded clues toward an immunopathological hypothesis. We finally speculate on future directions in relation to managing this severe toxicity and thereby optimizing the safe use of these drugs. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Many medicines are used "off‐label" in children outside the terms of the license. Feasible pediatric clinical trials are a challenge to design. Conect4children (c4c) is an Innovative Medicines Initiative project to set up a pan‐European pediatric clinical trial network aiming to facilitate the development of new medicines for children. To optimize pediatric trial development by promoting innovative trial design, c4c set up a European multidisciplinary advice service, including the voice of young patients and families, tailored to industry and academia. A network of experts was established to provide multidisciplinary advice to trial sponsors. Experts were selected to join clinical and innovative methodology expert groups. A patient and public involvement (PPI) database, to include the expert opinion of patients and parents/carers was formed. A stepwise process was developed: (1) sponsors contact c4c, (2) scoping interview takes place, (3) ad hoc advice group formed, (5) advice meeting held, and (6) advice report provided. Feedback on the process was collected. Twenty‐four clinical and innovative methodology expert groups (>400 experts) and a PPI database of 135 registrants were established. As of September 30, 2022, 36 advice requests were received, with 25 requests completed. Clinical and methodology experts and PPI representatives participated in several advice requests. Sponsors appreciated the advice quality and the multidisciplinary experts from different countries, including experts not known before. Experts and PPI participants were generally satisfied with the process. The c4c project has shown successful proof of concept for a service that presents a new framework to plan innovative and feasible pediatric trials. [ABSTRACT FROM AUTHOR]

Introduction and Objective: Proton pump inhibitor (PPI) use in children increases the risk of infections, prompting inquiry into the impact of prenatal PPIs exposure on serious infections in offspring. As a research gap in this area exists, this study aimed to address it by assessing the association between prenatal PPIs exposure and serious infections in infants during their first year of life.Using the French health insurance data warehouse (SNDS) (2013–2018), we conducted a retrospective cohort study on singleton, full-term liveborn non-immunocompromised infants, stratified by PPI use during the first three months of life (early-life use). Proton pump inhibitor dispensing in ambulatory care settings during pregnancy defined exposure. Outcomes concerned any serious infections in offspring aged between 3 and 12 months. Adjusted odds ratios (aORs) were estimated using logistic regression with multivariable models to control for potential confounders.Of the 2,485,545 infants included, 497,060 (23.3%) were prenatally exposed to PPIs and 97,767 (4.6%) had PPI use during the first three months of life. Prenatal PPI exposure was associated with serious infections in offspring (aOR, 1.09 [95% CI, 1.07–1.10]) in infants without early-life PPIs use. No association was found for infants with early-life PPI use (aOR, 1.05 [95% CI, 1.00–1.11]). Gastrointestinal infections were the sole site with persistent significance.Prenatal PPI exposure is common and is not associated with a major risk of serious infections in infants during their first year. However, even after adjusting for several confounding factors, a weak association remains, especially in infants without early-life PPI use. While offering reassurance, adherence to clinical guidelines is still crucial.Methods: Proton pump inhibitor (PPI) use in children increases the risk of infections, prompting inquiry into the impact of prenatal PPIs exposure on serious infections in offspring. As a research gap in this area exists, this study aimed to address it by assessing the association between prenatal PPIs exposure and serious infections in infants during their first year of life.Using the French health insurance data warehouse (SNDS) (2013–2018), we conducted a retrospective cohort study on singleton, full-term liveborn non-immunocompromised infants, stratified by PPI use during the first three months of life (early-life use). Proton pump inhibitor dispensing in ambulatory care settings during pregnancy defined exposure. Outcomes concerned any serious infections in offspring aged between 3 and 12 months. Adjusted odds ratios (aORs) were estimated using logistic regression with multivariable models to control for potential confounders.Of the 2,485,545 infants included, 497,060 (23.3%) were prenatally exposed to PPIs and 97,767 (4.6%) had PPI use during the first three months of life. Prenatal PPI exposure was associated with serious infections in offspring (aOR, 1.09 [95% CI, 1.07–1.10]) in infants without early-life PPIs use. No association was found for infants with early-life PPI use (aOR, 1.05 [95% CI, 1.00–1.11]). Gastrointestinal infections were the sole site with persistent significance.Prenatal PPI exposure is common and is not associated with a major risk of serious infections in infants during their first year. However, even after adjusting for several confounding factors, a weak association remains, especially in infants without early-life PPI use. While offering reassurance, adherence to clinical guidelines is still crucial.Results: Proton pump inhibitor (PPI) use in children increases the risk of infections, prompting inquiry into the impact of prenatal PPIs exposure on serious infections in offspring. As a research gap in this area exists, this study aimed to address it by assessing the association between prenatal PPIs exposure and serious infections in infants during their first year of life.Using the French health insurance data warehouse (SNDS) (2013–2018), we conducted a retrospective cohort study on singleton, full-term liveborn non-immunocompromised infants, stratified by PPI use during the first three months of life (early-life use). Proton pump inhibitor dispensing in ambulatory care settings during pregnancy defined exposure. Outcomes concerned any serious infections in offspring aged between 3 and 12 months. Adjusted odds ratios (aORs) were estimated using logistic regression with multivariable models to control for potential confounders.Of the 2,485,545 infants included, 497,060 (23.3%) were prenatally exposed to PPIs and 97,767 (4.6%) had PPI use during the first three months of life. Prenatal PPI exposure was associated with serious infections in offspring (aOR, 1.09 [95% CI, 1.07–1.10]) in infants without early-life PPIs use. No association was found for infants with early-life PPI use (aOR, 1.05 [95% CI, 1.00–1.11]). Gastrointestinal infections were the sole site with persistent significance.Prenatal PPI exposure is common and is not associated with a major risk of serious infections in infants during their first year. However, even after adjusting for several confounding factors, a weak association remains, especially in infants without early-life PPI use. While offering reassurance, adherence to clinical guidelines is still crucial.Conclusion: Proton pump inhibitor (PPI) use in children increases the risk of infections, prompting inquiry into the impact of prenatal PPIs exposure on serious infections in offspring. As a research gap in this area exists, this study aimed to address it by assessing the association between prenatal PPIs exposure and serious infections in infants during their first year of life.Using the French health insurance data warehouse (SNDS) (2013–2018), we conducted a retrospective cohort study on singleton, full-term liveborn non-immunocompromised infants, stratified by PPI use during the first three months of life (early-life use). Proton pump inhibitor dispensing in ambulatory care settings during pregnancy defined exposure. Outcomes concerned any serious infections in offspring aged between 3 and 12 months. Adjusted odds ratios (aORs) were estimated using logistic regression with multivariable models to control for potential confounders.Of the 2,485,545 infants included, 497,060 (23.3%) were prenatally exposed to PPIs and 97,767 (4.6%) had PPI use during the first three months of life. Prenatal PPI exposure was associated with serious infections in offspring (aOR, 1.09 [95% CI, 1.07–1.10]) in infants without early-life PPIs use. No association was found for infants with early-life PPI use (aOR, 1.05 [95% CI, 1.00–1.11]). Gastrointestinal infections were the sole site with persistent significance.Prenatal PPI exposure is common and is not associated with a major risk of serious infections in infants during their first year. However, even after adjusting for several confounding factors, a weak association remains, especially in infants without early-life PPI use. While offering reassurance, adherence to clinical guidelines is still crucial. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 V1 and V2. 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. [ABSTRACT FROM AUTHOR]

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/m2 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/m2 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. [ABSTRACT FROM AUTHOR]

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. • This LC-MS/MS method allows to quantify ivacaftor, lumacaftor, elexacaftor, tezacaftor and two metabolites of ivacaftor. • This assay requires only 100 µL of plasma from patients. • This method has been successfully applied to routine analysis and clinical research. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Ibuprofen is a nonsteroidal anti-inflammatory agent that induces closure of the patent ductus arteriosus in neonates. • Few studies of ibuprofen pharmacokinetics have been performed and were limited to small groups of preterm infants, showing a large intersubject variability and an increase in clearance with either postnatal or gestational age. WHAT THIS STUDY ADDS • A population pharmacokinetic study was performed on 66 neonates to characterize the concentration-time courses of ibuprofen. • Ibuprofen clearance significantly increased from postnatal age day 1 to day 8, but not with gestational age. • A relationship was shown between ibuprofen area under the curve (AUC) and patent ductus arteriosus closure rate, and an effective threshold AUC was evidenced. • Dosing schemes were proposed as a function of postnatal age, to achieve this AUC and to improve the efficacy of treatment for patent ductus arteriosus in neonates. AIMS To describe ibuprofen pharmacokinetics in preterm neonates with patent ductus arteriosus (PDA) and to establish relationships between doses, plasma concentrations and ibuprofen efficacy and safety. METHODS Sixty-six neonates were treated with median daily doses of 10, 5 and 5 mg kg−1 of ibuprofen-lysine by intravenous infusion on 3 consecutive days. A population pharmacokinetic model was developed with NONMEM. Bayesian individual pharmacokinetic estimates were used to calculate areas under the curve (AUC) and to simulate doses. A logistic regression was performed on PDA closure. RESULTS Ibuprofen pharmacokinetics were described by a one-compartment model with linear elimination. Mean population pharmacokinetic estimates with corresponding intersubject variabilities (%) were: elimination clearance CL = 9.49 ml h−1 (62%) and volume of distribution V = 375 ml (72%). Ibuprofen CL significantly increased with postnatal age (PNA): CL = 9.49*(PNA/96.3)1.49. AUC after the first dose (AUC1D), the sum of AUC after the three doses (AUC3D) and gestational age were significantly higher in 57 neonates with closing PDA than in nine neonates without PDA closure ( P = 0.02). PDA closure was observed in 50% of the neonates when AUC1D < 600 mg l−1 h (or AUC3D < 900 mg l−1 h) and in 91% when AUC1D > 600 mg l−1 h (or AUC3D > 900 mg l−1 h) ( P = 0.006). No correlation between AUC and side-effects could be demonstrated. CONCLUSIONS To achieve these optimal AUCs, irrespective of gestational age, three administrations at 24 h intervals are recommended of 10, 5, 5 mg kg−1 for neonates younger than 70 h, 14, 7, 7 mg kg−1 for neonates between 70 and 108 h and 18, 9, 9 mg kg−1 for neonates between 108 and 180 h. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Discusses the predictive factors of virologic success in HIV-positive children treated with the protease inhibitor lopinavir/ritonavir (LPV). Longitudinal single-center observational study; CD4 percentage; HIV-1 RNA level; Viral load; Baseline LPV mutation score; Plasma LPV maximal concentration.

The pharmacokinetics of isoniazid (INH) was studied in children (0-196 months old) according to their acetylator phenotype, estimated from the metabolic acetyl INH/INH molar plasma concentration ratio (MR) measured 3 h after INH oral administration. There were 17 slow (MR < 0.48) and 17 fast acetylators (MR ≥ 0.48). The mean apparent plasma clearance was significantly lower, the mean apparent volume of distribution higher and the half-life longer in the slow acetylator group (C1, 0.298 ± 0.099 L/h/kg; Vd, 1.56 ± 0.65 L/kg; t1/2, 3.88 ± 01.89 h) than in the fast acetylator group (Cl, 0.528 ± 0.234 L/h/kg; Vd, 1.06 ± 0.45; t1/2, 1.64 ± 1.1 h). The half-life decreased with age. An impaired isoniazid elimination was suggested in children less than three months old, which may be in favour of an individual dose adjustment in this population. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Excess of acute kidney injury (AKI) secondary to the association of vancomycin plus piperacillin is debated.Objectives: To detect a signal for an increased risk of AKI with the vancomycin and piperacillin combination compared with other vancomycin-based regimens.Methods: Using VigiBase, the WHO global database of individual case safety reports (ICSR) from 1997 to 2019, we conducted a disproportionality analysis comparing the reporting of AKI cases between different vancomycin-based regimens (vancomycin plus piperacillin, cefepime or meropenem). To take into account a possible notoriety bias, we secondarily restricted the study period to before 2014, the date of the first publication of AKI in patients receiving vancomycin plus piperacillin. Results are expressed using the reporting OR (ROR) and its 95% CI.Results: From 1997 to 2019, 53 701 ICSR concerning vancomycin have been registered in the database, including 6016 reports of AKI (11.2%), among which 925 (15.4%) were reported with vancomycin/piperacillin, 339 (5.6%) with vancomycin/cefepime and 197 (3.7%) with vancomycin/meropenem. ROR (95% CI) for AKI was 2.6 (2.4-2.8) for vancomycin/piperacillin, 2.5 (2.2-2.9) for vancomycin/cefepime and 0.5 (0.4-0.6) for vancomycin/meropenem versus other vancomycin-containing regimens. After restriction of the study period to 1997-2013, the ROR for AKI remains significant only for vancomycin/piperacillin [ROR (95% CI) = 2.1 (1.8-2.4)].Conclusions: We found a disproportionality in reports of AKI in patients receiving vancomycin plus piperacillin compared with vancomycin in other regimens. This suggests a drug-drug interaction between these two antibiotics resulting in an increased risk of AKI. [ABSTRACT FROM AUTHOR]

Emergency departments (EDs) have a key role in the public health system. They are facing a constant growth of their volume. Forecasting the daily volume is a major tool to adapt the allocation of resources. In this paper, we focus on pediatric EDs. They are specific by their strong seasonal variation, determined by the academic pace. The main contribution of this paper is to integrate the effects of this pace to the annual seasonality. We also tried out to improve the daily forecasting by forecasting the week means of the flow first. We trained and tested these models specifically on the pediatric EDs of Paris university hospital trust. For the eight pediatric EDs gathered, on average for the years 2016 to 2019, we forecasted the daily volume with a Mean Absolute Percentage Error (MAPE) of 6.6% for a 7-days forecasting, 7.1% for a 14-days forecasting and 7.6% for a 28-days forecasting. Account of rhythm allows a performance increase, with results respectively 7%, 10.1% and 8.4% better relatively to a baseline model based on a periodic regression on the weeks. [ABSTRACT FROM AUTHOR]

Purpose: Progressive early-onset scoliosis raises major challenges for surgeons, as growth must be preserved. With traditional growing rods, the need for repeated surgery is associated with numerous complications, high costs, and heavy psychosocial burden on the patient and family. We assessed the safety and efficacy of a new one-way self-expanding rod (OWSER). Methods: This prospective single-centre phase 2 study included two groups of children with progressive EOS treated by the OWSER in 2016–2017: Ten received a unilateral construct to treat progressive non-neuromuscular curves and 10 others a bilateral construct for neuromuscular scoliosis. Clinical and radiological data were assessed at surgery and 3, 6, 12, 18 months later. The primary endpoint was success defined as the absence of repeated surgery at 12 months. Results: In the non-neuromuscular group, rod expansion occurred in 5 of 10 patients [95% CI 19–81]; in the five other patients, rotational conflict inside the domino prevented rod expansion, four of them required surgery within the first 12 months. Rod expansion occurred spontaneously and during monthly traction sessions in all 10 neuromuscular patients [95% CI 69–100], without mechanical or device-related complications. Residual pelvic obliquity was improved by −3° [− 6.0 to 9.5] at 18 months. Lung function improved in the non-neuromuscular group. Conclusion: In neuromuscular diseases, the OWSER bilateral construct seems to be safe and less aggressive. Used as unilateral construct in non-neuromuscular group, it was less effective. Accordingly, we recommend the bilateral construct for all aetiologies. That device could avoid further surgery and reduce the rate of complications after long follow-up. [ABSTRACT FROM AUTHOR]

The article discusses a global pharmacovigilance study on the risk of giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) following COVID-19 vaccination. Topics covered include the use of VigiBase, the World Health Organization global individual case safety report database, how the association between an adverse event and a specific drug is assessed and the risk compared with influenza vaccination. It also discusses the limitations of the study and the potential safety signal.

Coronavirus disease 2019 (COVID-19) is characterized by distinct patterns of disease progression that suggest diverse host immune responses. We performed an integrated immune analysis on a cohort of 50 COVID-19 patients with various disease severity. A distinct phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-b and low IFN-a production and activity), which was associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor nuclear factor–kB and characterized by increased tumor necrosis factor–a and interleukin-6 production and signaling. These data suggest that type I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background Acute kidney injury (AKI) is frequent in patients resuscitated from cardiac arrest (CA) and may worsen outcome. Experimental data suggest a renoprotective effect by treating these patients with a high dose of erythropoietin (Epo) analogues. We aimed to evaluate the efficacy of epoetin alpha treatment on renal outcome after CA. Methods We did a post hoc analysis of the Epo-ACR-02 trial, which randomized patients with a persistent coma after a witnessed out-of-hospital CA. Only patients admitted in one intensive care unit were analysed. In the intervention group, patients received five intravenous injections of Epo spaced 12 h apart during the first 48 h, started as soon as possible after resuscitation. In the control group, patients received standard care without Epo. The main endpoint was the proportion of patients with persistent AKI defined by Kidney Disease: Improving Global Outcomes criteria at Day 2. Secondary endpoints included the occurrence of AKI through Day 7, estimated glomerular filtration rate (eGFR) at Day 28, haematological indices and adverse events. Results A total of 162 patients were included in the primary analysis (74 in the Epo group, 88 in the control group). Baseline characteristics were similar in the two groups. At Day 2, 52.8% of the patients (38/72) in the intervention group had an AKI, as compared with 54.4% of the patients (46/83) in the control group (P = 0.74). There was no significant difference between the two groups regarding the proportion of patients with AKI through Day 7. Among patients with persistent AKI at Day 2, 33% (4/12) in the intervention group had an eGFR <75 mL/min/1.73 m2 compared with 25% (3/12) in the control group at Day 28 (P = 0.99). We found no significant differences in haematological indices or adverse events. Conclusion After CA, early administration of Epo did not confer any renal protective effect as compared with standard therapy. [ABSTRACT FROM AUTHOR]

Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss and death due to bleeding after trauma and post‐partum haemorrhage. One key issue for treatment success is early administration. While usually given intravenously, oral and intramuscular use would be useful in specific circumstances. Therefore, an understanding of TXA pharmacokinetics when given via different routes is valuable. The aim of this study was to perform an individual participant data meta‐analysis of pharmacokinetic studies with TXA given to healthy volunteers via different routes. We searched the following databases: PubMed, Web of Science, Wiley Online Library, Elsevier Science Direct and J‐STAGE. Individual subject data were extracted when available, otherwise arithmetic means were used. A population pharmacokinetic model was developed using nonlinear mixed effect modelling. Seven studies were included in the analysis with data from 10 patients for the IV route, six patients for the IM route and 114 patients for the oral route. The pharmacokinetics was ascribed to a two‐compartment model, and the main covariate was allometrically scaled bodyweight. Oral and IM bioavailabilities were 46 and 105%, respectively. For a 70 kg bodyweight, the population estimates were 7.6 L/h for clearance, 17.9 L for the volume of the central compartment, 2.5 L/h for the diffusional clearance and 16.6 L for the peripheral volume of distribution. Larger well‐designed studies are needed to describe the pharmacokinetics of TXA when given IM or as an oral solution before these can be recommended as alternatives to IV. [ABSTRACT FROM AUTHOR]

Background: To access the long term relationship between efavirenz plasma concentrations and evolution of HIV RNA loads and CD4 cell counts in children. Methods: Retrospective analysis of data from HIV-infected children on first line efavirenz-containing regimen. A population pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe the evolution of HIV RNA load and CD4 cell count (efficacy outcomes) in relation to efavirenz plasma concentration. Individual CYP2B6 516 G>T genotype data were not available for this analysis. A score (ISEFV) quantifying the effect of efavirenz concentrations on the long-term HIV replication was calculated from efavirenz concentrations and PD parameters and, a value of ISEFV below which HIV replication is likely not suppressed was determined. Cox proportional hazards regression models were used to assess the association of the risk of viral replication with ISEFV, and with efavirenz mid-dose concentration(C12). Results: At treatment initiation, median (interquartile range, IQR) age was 8 years (5 to 10), body weight 17 kg (14 to 23), HIV RNA load 5.1 log10 copies/mL (4.6 to 5.4), and CD4 cell count 71 cells/mm3. A model of PK-PD viral dynamics assuming that efavirenz decreases the rate of infected host cells adequately described the relationship of interest. After adjusting for age, baseline HIV RNA load and CD4 cell counts an ISEFV <85% was significantly associated with a higher risk of viral replication (p-value <0.001) while no significant association was observed with C12 <1.0 mg/L. Conclusion: The ISEFV score was a good predictor of viral replication in children on efavirenz-based treatment. [ABSTRACT FROM AUTHOR]

Enoxaparin is commonly used in the prevention of renal allograft vascular thrombosis but off‐label in children, and no consensus exists regarding the optimal dosing and dose adjustment. In this retrospective study, 444 anti‐Xa levels were obtained from 30 pediatric renal transplant recipients in order to investigate enoxaparin population pharmacokinetics. The main results were (1) 25% of children achieved the target anti‐Xa activity 36 hours after initiation of treatment, (2) anti‐Xa time courses were best described by a 1‐compartment open model with first‐order absorption, (3) body weight but not renal function was the sole covariate influencing clearance and volume of distribution, and (4) large between‐subject and between‐occasion variabilities in anti‐Xa activity were observed. However, creatinine‐based estimated glomerular filtration rate in the first post–renal transplantation hours may not reliably reflect the actual renal function of the children. Based on the final population model, a Bayesian‐based program was developed in order to estimate the individual pharmacokinetic parameters on a single anti‐Xa measurement, allowing determination of the next enoxaparin dose that will quickly achieve an appropriate anti‐Xa activity (targeting 0.3‐0.5 IU/mL) and anticoagulation. Finally, these results should help standardize practices that remain to date largely heterogeneous in pediatric intensive care units. [ABSTRACT FROM AUTHOR]

Objectives To describe cidofovir pharmacokinetics and assess the link between concentration and safety/efficacy in children. Patients and methods An observational study was conducted in 13 immunocompromised children receiving cidofovir for adenovirus and/or cytomegalovirus infection. A population pharmacokinetic model was built and AUC0–24 was derived for each patient. Virological success was defined as a decrease of the viraemia by ≥1 log10 copies/mL within 15 days of cidofovir initiation. The association between AUC0–24 and virological success was assessed using a Wilcoxon test. An AUC0–24 cut-off value was determined using a Fisher’s exact test. Results Overall, 86 blood samples were analysed. A two-compartment model with first-order absorption and elimination best described the cidofovir data. Virological success (VS) was reached in 6/8 children with adenovirus viraemia and in 1/4 children with cytomegalovirus viraemia. Patients with VS displayed a non-significant higher median AUC0–24 compared with patients with virological failure: 48.6 (range 8.9–72.6) versus 19.1 (6.9–22.7) mg·h/L. Adenovirus-viraemic patients with an AUC0–24 value below 19.1 mg·h/L had a higher probability of treatment failure (P  = 0.03). Aviraemic children with stool and/or nasopharyngeal adenovirus carriage cleared the viral carriage within a month of cidofovir initiation. During treatment, 1/13 children developed a tubulopathy but none of them had an increase in creatininaemia. Conclusions Cidofovir appears safe and reasonably well tolerated and seemed to have efficacy in a subset of patients with adenovirus/cytomegalovirus infection. Therapeutic drug monitoring may be useful in children receiving cidofovir and, in the case of adenovirus infection, targeting an AUC0–24 above 19.1 mg·h/L could be associated with higher probability of virological success. [ABSTRACT FROM AUTHOR]

Purpose: Sepsis and non-septic systemic inflammatory response syndrome (SIRS) are the same syndromes, differing by their cause, sepsis being secondary to microbial infection. Microbiological tests are not enough to detect infection early. While more than 50 biomarkers have been proposed to detect infection, none have been repeatedly validated.Aim: To assess the accuracy of circulating biomarkers to discriminate between sepsis and non-septic SIRS.Methods: The CAPTAIN study was a prospective observational multicenter cohort of 279 ICU patients with hypo- or hyperthermia and criteria of SIRS, included at the time the attending physician considered antimicrobial therapy. Investigators collected blood at inclusion to measure 29 plasma compounds and ten whole blood RNAs, and-for those patients included within working hours-14 leukocyte surface markers. Patients were classified as having sepsis or non-septic SIRS blindly to the biomarkers results. We used the LASSO method as the technique of multivariate analysis, because of the large number of biomarkers.Results: During the study period, 363 patients with SIRS were screened, 84 having exclusion criteria. Ninety-one patients were classified as having non-septic SIRS and 188 as having sepsis. Eight biomarkers had an area under the receiver operating curve (ROC-AUC) over 0.6 with a 95% confidence interval over 0.5. LASSO regression identified CRP and HLA-DRA mRNA as being repeatedly associated with sepsis, and no model performed better than CRP alone (ROC-AUC 0.76 [0.68-0.84]).Conclusions: The circulating biomarkers tested were found to discriminate poorly between sepsis and non-septic SIRS, and no combination performed better than CRP alone. [ABSTRACT FROM AUTHOR]

Aims: Preventing post‐liver transplantation (LT) hepatic artery and portal vein thrombosis includes enoxaparin administration. Enoxaparin pharmacokinetics (PK) has not been investigated in children following LT. We described an enoxaparin PK model in 22 children the first week following LT. Methods: Anti‐Xa activity time‐courses were analysed using a nonlinear mixed effects approach with Monolix version 2016R. Results: Anti‐Xa activity time‐courses were well described by a one‐compartment model with first order absorption and elimination. Bodyweight prior to surgery (BWPREOP) and the related postoperative variation (BW(t)) were the main covariates explaining CL and V between subject variabilities. Parameter estimates were CLi = CLTYP * (BWPREOP/70)3/4; Vi = VTYP * (BW(t)/70)1; where typical clearance (CLTYP) and typical volume of distribution (VTYP) were 1.23 l h−1 and 14.6 l, respectively. Standard dosing regimens of 50 IU kg−1 12 h−1 were insufficient to reach the target range of anti‐Xa activity of 0.2–0.4 IU ml−1. Specifically, seven children (32%) never attained the target range during the whole period of treatment and all children were at least once underdosed. According to the final results, we simulated individualized dosing regimens within 4 h following the first administration. More than 100 IU kg−1 12 h−1 are suggested to reach the target range of anti‐Xa activity of 0.2–0.4 IU ml−1 from the first day. Conclusion: Thanks to this model, the initial and maintenance doses could be assessed to rapidly achieve the target range. Higher doses per kg, especially in the youngest children, are suggested. [ABSTRACT FROM AUTHOR]