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International audience; 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; NCT 03777488.

Background Mass indoor gatherings were banned in early 2020 to prevent the spread of SARS-CoV-2. We aimed to assess, under controlled conditions, whether infection rates among attendees at a large, indoor gathering event would be similar to those in non-attendees, given implementation of a comprehensive prevention strategy including antigen-screening within 3 days, medical mask wearing, and optimised ventilation. Methods The non-inferiority, prospective, open-label, randomised, controlled SPRING trial was done on attendees at a live indoor concert held in the Accor Arena on May 29, 2021 in Paris, France. Participants, aged 18–45 years, recruited via a dedicated website, had no comorbidities, COVID-19 symptoms, or recent case contact, and had had a negative rapid antigen diagnostic test within 3 days before the concert. Participants were randomly allocated in a 2:1 ratio to the experimental group (attendees) or to the control group (non-attendees). The allocation sequence was computer-generated by means of permuted blocks of sizes three, six, or nine, with no stratification. The primary outcome measure was the number of patients who were SARS-CoV-2-positive by RT-PCR test on self-collected saliva 7 days post-gathering in the per-protocol population (non-inferiority margin

Contains fulltext : 289893.pdf (Publisher’s version ) (Open Access) Differences in disability perception between patients and care providers may impact outcomes. We aimed to explore differences in disability perception between patients and care providers in systemic sclerosis (SSc). We conducted a cross-sectional internet-based mirror survey. SSc patients participating in the online SPIN Cohort and care providers affiliated with 15 scientific societies were surveyed using the Cochin Scleroderma International Classification of Functioning, Disability and Health (ICF)-65 questionnaire, including 65 items (from 0 to 10), representing 9 domains of disability. Mean differences between patients and care providers were calculated. Care providers' characteristics associated with a mean difference >= 2 of 10 points were assessed in multivariate analysis. Answers were analyzed for 109 patients and 105 care providers. The mean age of patients was 55.9 (14.7) years and the disease duration was 10.1 (7.5) years. For all domains of the ICF-65, care providers' rates were higher than those of patients. The mean difference was 2.4 (1.0) of 10 points. Care providers' characteristics associated with this difference were organ-based specialty (OR = 7.0 [2.3-21.2]), younger age (OR = 2.7 [1.0-7.1]) and following patients with disease duration >= 5 years (OR = 3.0 [1.1-8.7]). We found systematic differences in disability perception between patients and care providers in SSc. 10 p.

We aimed to develop a piperacillin population pharmacokinetic (PK) model in critically ill children receiving continuous renal replacement therapy (CRRT) and to optimize dosing regimens. The piperacillin plasma concentration was quantified by high-performance liquid chromatography. Piperacillin PK was investigated using a nonlinear mixed-effect modeling approach. Monte Carlo simulations were performed to compute the optimal scheme of administration according to the target of 100% interdose interval time in which concentration is one to four times above the MIC (100% fT > 1 to 4× MIC). A total of 32 children with a median (interquartile range [IQR]) postnatal age of 2 years (0 to 11), body weight (BW) of 15 kg (6 to 38), and receiving CRRT were included. Concentration-time courses were best described by a one-compartment model with first-order elimination. BW and residual diuresis (Q(u)) explained some between-subject variabilities on volume of distribution (V), where [Image: see text] , and clearance (CL), where [Image: see text] , where CL(pop) and V(pop) are 6.78 L/h and 55.0 L, respectively, normalized to a 70-kg subject and median residual diuresis of 0.06 mL/kg/h. Simulations with intermittent and continuous administrations for 4 typical patients with different rates of residual diuresis (0, 0.1, 0.25, and 0.5 mL/kg/h) showed that continuous infusions were appropriate to attain the PK target for patients with residual diuresis higher than 0.1 mL/kg/h according to BW and MIC, while for anuric patients, less frequent intermittent doses were mandatory to avoid accumulation. Optimal exposure to piperacillin in critically ill children on CRRT should be achieved by using continuous infusions with escalating doses for high-MIC bacteria, except for anuric patients who require less frequent intermittent doses.

Glucocorticoids are 1 of the primary treatments in paediatric kidney transplantation. The aims of this study were: (i) to build a population pharmacokinetics (PPK) model of free prednisolone, which is the active form of prednisone, in paediatric kidney transplant recipients; (ii) to identify covariates accounting for interindividual variability (IIV) of pharmacokinetics (PK) parameters; and (iii) to investigate drug exposure-safety relationships.Ninety-seven samples were obtained from 39 paediatric kidney transplant recipients (aged 3.4-17.2 years) in order to investigate prednisone PPK. We selected children receiving oral prednisone as part of their immunosuppressive regimen. A PPK analysis was performed using Monolix.A 1-compartment model best described prednisolone concentrations. Large IIV was observed as prednisolone was undetectable at H12 in some patients but could still be detected at H24 in others. Both bodyweight and ciclosporin cotreatment influenced the PK. The clearance (CLThis study is the first analysis of prednisolone PPK in kidney-transplanted children. Some of the IIV in the PK parameters was explained by bodyweight and ciclosporin cotreatment. These data suggest that dose adjustment is required after identifying variability factors to optimize efficacy and limit side effects. The use of therapeutic drug monitoring in kidney-transplanted children may be useful, especially with respect to safety issues.

We aimed to develop a meropenem population pharmacokinetic model in critically ill children receiving continuous renal replacement therapy and simulate dosing regimens to optimize patient exposure.Meropenem plasma concentration was quantified by high-performance liquid chromatography. Meropenem pharmacokinetics was investigated using a non-linear mixed-effect modeling approach. Monte Carlo simulations were performed to compute the optimal scheme of administration, according to the target of a 100% inter-dose interval time in which concentration is one to four times above the minimum inhibitory concentration (100% fT1-4×MIC).A total of 27 patients with a median age of 4 [interquartile range 0-11] years, a median body weight of 16 [range 7-35] kg receiving continuous renal replacement therapy were included. Concentration-time courses were best described by a one-compartment model with first-order elimination. Body weight (BW) produced significant effects on volume of distribution (V) and BW and continuous renal replacement therapy effluent flow rate (QMeropenem exposure in critically ill children receiving continuous renal replacement therapy needs dosing adjustments to the minimum inhibitory concentration that take into account body weight and the continuous renal replacement therapy effluent flow rate.

In preterm infants, a high risk of hemodynamically significant patent ductus arteriosus (PDA) exists and its persistence is associated with an increased risk of severe morbidity. Current pharmacological options include ibuprofen or indomethacin. However, treatment by indomethacin or ibuprofen of a large PDA was shown to reduce early pulmonary hemorrhage and later medical treatment but had no effect on neonatal death or morbidity. Early prophylactic treatment of ductus arteriosus by paracetamol seems to be an attractive opportunity to reduce life-threatening morbidity. However, there are currently no data regarding the pharmacokinetics (PK) and pharmacodynamics of paracetamol in preterm neonates in this potential new indication. In this study, we aimed to develop a population PK model for paracetamol and investigate the relationship between paracetamol exposure levels and time to contraction of the ductus. Data were modeled using Monolix software. A one-compartment model adequately described the paracetamol concentration-time course. A Weibull model adequately described the time to contraction of the ductus. Our results suggest that the dosage used in this study (i.e., first day 42.5 mg/kg, then 30 mg/kg/day) allows for reaching the maximum inhibition response from paracetamol regarding the time to close the ductus. However, this study pointed out a lower effect of paracetamol on extremely preterm neonates (below 27 weeks). Therefore, a dose-finding study focusing specifically on extremely preterm neonates with treatment efficacy and toxicity is strongly needed.

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

International audience; Despite antenatal corticosteroids therapy, respiratory distress syndrome (RDS) is still a leading cause of neonatal morbidity and mortality in premature newborns. To date, the relationship between in utero fetal drug exposure and occurrence of RDS remains poorly evaluated. This study aims to describe the pharmacokinetics of betamethasone in pregnant women and to evaluate the transplacental drug transfer and administration scheme for the prevention of RDS. Pregnant women > 27 weeks' gestation and who received at least a single dose of betamethasone for prevention of RDS were enrolled. Maternal, cord blood, and amniotic fluid betamethasone time-courses were analyzed using the Monolix software. A total of 220 maternal blood, 56 cord blood, and 26 amniotic fluid samples were described by a two-compartment model with two effect compartments linked by rate transfer constants. Apparent clearances and volumes of distribution parameters were allometrically scaled for a 70 kg third trimester pregnant woman. The impact of a twin pregnancy was found to increase maternal clearance by 28%. Using a fetal-to-mother exposure ratio, the median (95% confidence interval (CI)) transplacental transfer of betamethasone was estimated to 35% (95% CI 0.11-0.67). After adjustment for gestational age and twin pregnancy, RDS was found to be associated to the time spent in utero below quantifiable concentrations (i.e., < 1 ng/mL): odds ratio of 1.10 (95% CI 1.01-1.19) per day increase (P < 0.05). Trying to take into account both efficacy and safety, we simulated different dosing schemes in order to maintain a maximum of fetuses above 1 ng/mL without exceeding the total standard dose.

Background Patient-reported outcome measures (PROMs) aimed at assessing people with systemic sclerosis (SSc) have rarely involved the target population in the item- and domain-generation stage of the instrument construction. Objectives To develop a new PROM assessing activities and participation in people with SSc. Methods A provisional International Classification of Functioning, Disability and Health (ICF)-based 65-item questionnaire previously developed from interviews of people with SSc was sent by email to all patients followed in the internal medicine department of Cochin hospital (n = 184) and enrolled in the Scleroderma Patient-centered Intervention Network Cohort. Items were reduced according to their metric properties. Dimensional structure of the questionnaire was assessed by principal component analysis, convergent and divergent validities by Spearman's rank correlation coefficient, internal consistency by Cronbach's α, and reliability by a test-retest method using the intraclass correlation coefficient (ICC) and Bland-Altman analysis. Results Overall, 113 of 184 patients (61·4%) completed the provisional questionnaire. The item-reduction process resulted in a 17-item questionnaire, the Cochin 17-item Scleroderma Functional scale (CSF-17). Principal component analysis extracted two dimensions: 10 items related to mobility (CSF-17 section A) and seven items related to general tasks (CSF-17 section B). We observed convergent validity of the CSF-17 total score with global activity limitation, pain, depression and aesthetic burden, and divergent validity with anxiety. Cronbach's α was 0·94 for section A and 0·95 for section B. ICC (n = 25 patients) was 0·92 for the CSF-17 total score. Bland-Altman analysis did not reveal a systematic trend for the test-retest. Conclusions The CSF-17 is a new PROM assessing activities and participation specifically in people with SSc. Its content and construct validities are very high. What is already known about this topic? In the earliest stages of construction patient-reported outcomes (PROMs) for people with systemic sclerosis (SSc) rarely involve the target population. Instruments able to capture the specific needs of people with SSc in terms of activities and participation are lacking. What does this study add? The Cochin 17-item Scleroderma Functional Scale (CSF-17) is a new PROM assessing global activities and participation specifically in people with SSc. Patients' perspectives were prioritized at all stages of construction. What are the clinical implications of this work? The CSF-17 could be used in clinical practice and research to assess the efficacy of complex multidisciplinary interventions targeting activity limitations and participation restriction in people with SSc. Linked Comment: Clark and Denton. Br J Dermatol 2020; 183:610.

Background Few pharmacokinetic data were reported on dispersible tablets despite their increasing use. One hundred fifty HIV-infected children receiving lamivudine were enrolled in the MONOD ANRS 12,206 trial. Three galenic forms were administered: liquid formulation, tablet form and dispersible scored tablet. Method HIV-infected children Results One hundred and fifty children (age: 2.5 years (1.9–3.2), weight 11.1 (9.5–12.5) kg (median (IQR)) were included in this study. Over the study period, 79 received only the syrup form, 29 children switched from syrup form to tablet 3TC/AZT form, 36 from syrup to the orodispersible ABC/3TC form and two from the 3TC/AZT form to the orodispersible ABC/3TC form. The 630 lamivudine concentrations were best described by a two-compartment model allometrically scaled. Galenic form had no significant effect on 3TC pharmacokinetic. Conclusion This trial provided an opportunity to compare three galenic forms (liquid formulation, tablet form and dispersible scored tablet) of lamivudine in the target population of young HIV–1-infected children. Galenic form had no significant effect on lamivudine pharmacokinetics.

Aim : To assess the diagnostic performance of a simplified lung point-of-care ultrasound (POCUS) to confirm the correct positioning of an endotracheal tube (ETT) in a pediatric intensive care unit (PICU) used to chest radiography (CXR), and to compare the time to obtain the ETT position between POCUS and CXR. Methods : We conducted a single-center prospective study in critically ill children requiring urgent endotracheal intubation. Esophageal tube malposition was first avoided using auscultation and end-tidal CO2. The ETT position was assessed with CXR and lung POCUS using the lung sliding sign on a pleural window. All of the investigators had to read guidelines and received 1-h training on the technical aspects of lung sliding. The primary objective was the accuracy of POCUS in confirming correct nonselective endotracheal intubation as compared with CXR. Results : A total of 71 patients were included from December 2016 to November 2018. CXR identified proper nonselective ETT placement in 43 of 71 (61%) patients, while the rate for selective intubation was 39%. The sensitivity and specificity of POCUS as compared with CXR were 77% and 68%, respectively. Median time to POCUS was significantly shorter than CXR (2 min to perform POCUS, 10 min to obtain radiographs, p Conclusion : Pleural ultrasound, although faster than CXR, appears to be inadequate for identifying selective ETT after urgent intubation in a PICU less accustomed to this kind of ultrasound. In this heterogeneous and fragile population, timely POCUS may remain useful at the bedside as compared with auscultation, aiming at guiding optimal ETT placement and reducing respiratory complications, provided by trained physicians.

We aimed to develop a meropenem population pharmacokinetic (PK) model in critically ill children and simulate dosing regimens in order to optimize patient exposure. Meropenem plasma concentration was quantified by high-performance liquid chromatography. Meropenem PK was investigated using a non-linear mixed-effect modeling approach. Forty patients with an age of 16.8 (1.4–187.2) months, weight of 9.1 (3.8–59) kg, and estimated glomerular filtration rate (eGFR) of 151 (19–440) mL/min/1.73 m2 were included. Eleven patients received continuous replacement renal therapy (CRRT). Concentration-time courses were best described by a two-compartment model with first-order elimination. Body weight (BW), eGFR, and CRRT were covariates explaining the between-subject variabilities on central/peripheral volume of distribution (V1/V2), inter-compartment clearance (Q), and clearance (CL): V1i = V1pop × (BW/70)1, Qi = Qpop × (BW/70)0.75, V2i = V2pop × (BW/70)1, CLi = (CLpop × (BW/70)0.75) × (eGFR/100)0.378) for patients without CRRT and CLi = (CLpop × (BW/70)0.75) × 0.9 for patients with CRRT, where CLpop, V1pop, Qpop, and V2pop are 6.82 L/h, 40.6 L, 1 L/h, and 9.2 L respectively normalized to a 70-kg subject. Continuous infusion, 60 and 120 mg/kg per day, is the most adequate dosing regimen to attain the target of 50% fT > MIC and 100% fT > MIC for patients infected by bacteria with high minimum inhibitory concentration (MIC) value (> 4 mg/L) without risk of accumulation except in children with severe renal failure. Continuous infusion allows reaching the fT > MIC targets safely in children with normal or increased renal clearance.

Background: Drug prescriptions are usual during pregnancy, however, women and their fetuses still remain an orphan population with regard to drugs efficacy and safety. Most xenobiotics diffuse through the placenta and some of them can alter fetus development resulting in structural abnormalities, growth or functional deficiencies. Methods: To summarize the different methodologies developed towards the prediction of fetal drug exposure. Results: Neonatal cord blood concentration is the most specific measurement of the transplacental drug transfer at the end of pregnancy. Using the cord blood and mother drug concentrations altogether, drug exchanges between the mother and fetus can be modeled and quantified via a population pharmacokinetic analysis. Thereafter, it is possible to estimate the fetus exposure and the fetus-to-mother exposure ratio. However, the prediction of placental transfer before any administration to pregnant women is desirable. Animal studies remain difficult to interpret due to structural and functional inter-species placenta differences. The ex-vivo perfusion of the human placental cotyledon is the method of reference to study the human placental transfer of drugs because it is thought to mimic the functional placental tissue. However, extrapolation of data to in vivo situation remains difficult. Some research groups have extensively worked on physiologically based models (PBPK) to predict fetal drug exposure and showed very encouraging results. Conclusion: PBPK models appeared to be a very promising tool in order to predict fetal drug exposure in-silico. However, these models mainly picture the end of pregnancy and knowledge regarding both, development of the placental permeability and transporters is strongly needed.

Ganciclovir is indicated for curative or preventive treatment of cytomegalovirus (CMV) infections. This study aimed to characterize ganciclovir pharmacokinetics, following intravenous ganciclovir and oral valganciclovir administration, to optimize dosing schemes. All children aged

Acyclovir is an antiviral currently used for the prevention and treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. This study aimed to characterize the pharmacokinetics (PK) of acyclovir and its oral prodrug valacyclovir to optimize dosing in children. Children receiving acyclovir or valacyclovir were included in this study. PK were described using nonlinear mixed-effect modeling. Dosing simulations were used to obtain trough concentrations above a 50% inhibitory concentration for HSV or VZV (0.56 mg/liter and 1.125 mg/liter, respectively) and maximal peak concentrations below 25 mg/liter. A total of 79 children (212 concentration-time observations) were included: 50 were taking intravenous (i.v.) acyclovir, 22 were taking oral acyclovir, and 7 were taking both i.v. and oral acyclovir, 57 for preventive and 22 for curative purposes. A one-compartment model with first-order elimination best described the data. An allometric model was used to describe body weight effect, and the estimated glomerular filtration rate (eGFR) was significantly associated with acyclovir elimination. To obtain target maximal and trough concentrations, the more suitable initial acyclovir i.v. dose was 10 mg/kg of body weight/6 h for children with normal renal function (eGFR ≤ 250 ml/min/1.73 m(2)) and 15 to 20 mg/kg/6 h for children with augmented renal clearance (ARC) (eGFR > 250 ml/min/1.73 m(2)). The 20-mg/kg/8 h dose for oral acyclovir and valacyclovir produced effective concentrations in more than 75% of children; however, a 15-mg/kg/6 h dose, if possible, is preferred. These doses should be prospectively confirmed, and therapeutic drug monitoring could be used to refine them individually. (This study has been registered at ClinicalTrials.gov under identifier NCT02539407.)

A population pharmacokinetic model was developed to explore the pharmacokinetics modification of unbound raltegravir during pregnancy. The RalFe ANRS160 study was a nonrandomized, open-label, multicenter trial enrolling HIV-infected pregnant women receiving a combined antiretroviral regimen containing 400 mg raltegravir twice daily. Biological samples were collected during the third trimester of pregnancy (between 30 and 37 weeks of gestational age) and at postpartum (4 to 6 weeks after delivery). A population pharmacokinetic model was developed with Monolix software. A total of 360 plasma samples were collected from 43 women during pregnancy and postpartum. The unbound raltegravir was described by a one-compartment model with a transit compartment with first-order absorption, evolving to bound raltegravir (by a linear binding to albumin) or metabolism to RAL-glucuronide or to a first-order elimination, with a circadian rhythm. During pregnancy, the absorption was decreased and delayed and the raltegravir elimination clearance and glucuronidation increased by 37%. Median total and unbound area under the curve from 0 to 12 h significantly decreased by 36% and 27% during pregnancy. Median total trough concentration (Ctrough) decreased significantly in the evening (28%); however, the median total Ctrough in the morning, unbound Ctrough in the morning, and unbound Ctrough in the evening showed a nonsignificant decrease of 16%, 1%, and 15%, respectively, during pregnancy compared to the postpartum period. This is the first study reporting the pharmacokinetics of unbound raltegravir during pregnancy. As unbound Ctrough did not significantly decrease during the third trimester, the pregnancy effect on raltegravir unbound concentrations was not considered clinically relevant. (This study has been registered at ClinicalTrials.gov under identifier {"type":"clinical-trial","attrs":{"text":"NCT02099474","term_id":"NCT02099474"}}NCT02099474.)

BackgroundPerinatal treatment with lopinavir boosted by ritonavir (LPV/r) is associated with steroidogenic abnormalities. Long-term effects in infants have not been studied.MethodsAdrenal-hormone profiles were compared at weeks 6 and 26 between human immunodeficiency virus (HIV)-1–exposed but uninfected infants randomly assigned at 7 days of life to prophylaxis with LPV/r or lamivudine (3TC) to prevent transmission during breastfeeding. LPV/r in vitro effect on steroidogenesis was assessed in H295R cells.ResultsAt week 6, 159 frozen plasma samples from Burkina Faso and South Africa were assessed (LPV/r group: n = 92; 3TC group: n = 67) and at week 26, 95 samples from Burkina Faso (LPV/r group: n = 47; 3TC group: n = 48). At week 6, LPV/r-treated infants had a higher median dehydroepiandrosterone (DHEA) level than infants from the 3TC arm: 3.91 versus 1.48 ng/mL (P < .001). Higher DHEA levels (>5 ng/mL) at week 6 were associated with higher 17-OH-pregnenolone (7.78 vs 3.71 ng/mL, P = .0004) and lower testosterone (0.05 vs 1.34 ng/mL, P = .009) levels in LPV/r-exposed children. There was a significant correlation between the DHEA and LPV/r AUC levels (ρ = 0.40, P = .019) and Ctrough (ρ = 0.40, P = .017). At week 26, DHEA levels remained higher in the LPV/r arm: 0.45 versus 0.13 ng/mL (P = .002). Lopinavir, but not ritonavir, inhibited CYP17A1 and CYP21A2 activity in H295R cells.ConclusionsLopinavir was associated with dose-dependent adrenal dysfunction in infants. The impact of long-term exposure and potential clinical consequences require evaluation.Clinical Trials RegistrationNCT00640263

International audience; Background: Bisphosphonates (BPs) are widely used for the prevention or treatment of osteoporosis. One of the most serious complications associated with BPs is medication-related osteonecrosis of the jaw (MRONJ) but its incidence in patients with osteoporosis is very low ranging from 0.001-0.15%. A major predisposing factor for MRONJ is tooth extraction (TE). Controversies persist about the influence of current BP therapy regarding socket healing after TE. The aims of this study were to investigate prospectively, (i) alveolar bone healing, i.e., filling of the bony socket by new bone and (ii) mucosal healing, i.e., closure of the overlying mucosa, after TE in women receiving current BP therapy for the prevention or the treatment of postmenopausal osteoporosis. Methods: Women with osteoporosis under current treatment with BPs (BP+ group) or other anti-osteoporotic medications (BP-group) undergoing single TE were included in this study. No antibiotic prophylaxis was prescribed solely for the BP therapy, but antibiotic treatment may have been required for local infectious conditions. Chlorohexidine mouthwashes were systematically prescribed in all study patients for one week after TE. New bone height (NBH) and rate of socket filling (RSF) were recorded using intraoral standardized radiographs one month and 3 months after TE (T30 and T90 respectively). The closure of the overlying mucosa was assessed by measuring the wound extent with an electronic caliper at 1 week and at 1 month after TE (T7 and T30 respectively). Results: At T30, NBH was not statistically different between the BP+ and BP-groups (p = .76). At T90, more than a twofold in NBH increase was recorded for both groups with no statistically significant difference between them (p = .76). At T30 and T90, RSF was similar in both groups (p = .58 and p = .32 respectively). More than a twofold RSF increase was founded between T30 and T90 in both groups. No demographic or BPs-related factors were correlated with the RSF at T90. At T7, the mucosa wound extent was reduced by more than twofold with no statistically significant difference between both groups (p = .80). At this time, mucosa healing was achieved in 11.9% of the BP+ group and 10% of the BP-group (p = .99). At T30, mucosal healing was achieved in all patients but two, and at T90 it was achieved in all patients. Conclusion: This study provides new insights into bone and mucosal healing in patients with osteoporosis taking BPs after TE. In this population, TE can be managed successfully with an appropriate surgical protocol and without discontinuation of BP treatment.

Dolutegravir, raltegravir and darunavir are three antiretroviral drugs widely used in combined antiretroviral therapies. These three drugs are highly bound to plasma proteins. Compared to the total concentration, the concentration of unbound drug which is considered as the only pharmacological active form should be more informative to improve therapeutic drug monitoring in patients to avoid virological failure or toxicity. The aim of the present study was to develop an ultrafiltration protocol and a LC-MS/MS method to simultaneously determine the concentrations of the unbound dolutegravir, raltegravir and darunavir in human plasma. Finally, 150 μL of plasma was ultrafiltrated using Centrifree® ultrafiltration devices with ultracel YM-T membrane (cutoff 30 KDa) during 5 min at 37 °C at 1500 g. Then, 20 μL of the ultrafiltrate were injected into the LC-MS/MS system. The chromatographic separation was carried out on a BEH C18 column using a mobile phase containing deionized water and acetonitrile, both with 0.05 % (v/v) of formic acid, with a gradient elution at a flow rate of 0.5 mL/min. The run time was only 4 min. The calibration curve ranged from 0.5-200 ng/mL for dolutegravir, 1 to 400 ng/mL for raltegravir and 10-4000 ng/mL for darunavir. This method was validated with a good precision (inter- and intra-day CV% lower than 14 %) and a good accuracy (inter- and intra-day bias between -5.6-8.8 %) for all the analytes. This method is simple, reliable and suitable for pharmacokinetic studies.

Therapeutic drug monitoring (TDM) is essential in the optimization of antiretroviral (ARV) treatments. In this work, we describe a new method for the simultaneous quantification of six molecules: the three novel ARV agents dolutegravir (DTG), elvitegravir (ELV) and rilpivirine (RPV), the first integrase inhibitor raltegravir (RAL) and its major metabolite the raltegravir-β- d -glucuronide (RAL-GLU), an protease inhibitor darunavir (DRV) and its booster ritonavir (RTV) in human plasma. The drugs were extracted from 100 μL of plasma by a simple method of protein precipitation using acetonitrile. The separation was carried out on a Kinetex phehyl-hexyl column using a phase mobile composed of 55 % of water (0.05 % formic acid,v/v) and 45 % of methanol (0.05 % formic acid,v/v). The flow rate was set at 0.5 mL/min. The calibration ranged from 60 to 15000 ng/mL for DRV, from 20 to 5000 ng/mL for DTG and ELV, from 10 to 2500 ng/mL for RAL, RAL-GLU, RTV and RPV. The proposed method was validated with a good precision (inter- and intra-day CV% inferior to 12.3 %) and a good accuracy (inter- and intra-day bias between −9.9 % and 10 %) for all the analytes. The proposed method is simple, reliable and suitable for therapeutic drug monitoring (TDM) and for pharmacokinetics studies.

Background The patient acceptable symptom state (PASS) is a treatment-response criterion developed to determine the clinical relevance of a treatment effect. Its estimates for some patient-reported outcomes (PROs) in non-specific chronic low back pain (cLBP) are lacking and the stability of PRO estimates between independent cLBP populations is unknown. We hypothesized that these PRO estimates will be stable. Objectives To estimate and compare the PASS for PROs between 2 independent cLBP populations. Methods We conducted a secondary analysis of a randomized controlled trial (PREDID) and a cohort of outpatients with non-specific cLBP. Using an anchoring question, participants who self-rated their health as “excellent”, “very good” or “good” at 1 month were considered to have an acceptable symptom state. PASS estimates for 5 PROs were calculated by using the 75th percentile method. Estimates were compared between the 2 populations with bootstrap resampling. Results A total of 256 participants with non-specific cLBP were included: 135 patients with cLBP and active discopathy from the PREDID trial and 121 outpatients with cLBP without active discopathy followed up in an independent cohort. Overall, 137/256 (54%) participants had an acceptable symptom state at 1 month. PASS estimates were 47.5 (95% confidence interval [CI] 40.0 to 50.0)/100 for lumbar pain (0, no pain and 100, maximal pain), 30.5 (30.0 to 40.0)/100 for radicular pain, 39.3 (33.6 to 45.3)/100 for Quebec Back Pain Disability score (0, no disability and 100, maximal disability), 10.0 (9.2 to 10.0)/21 for the Hospital Anxiety Depression anxiety subscale (0, no anxiety, and 21, maximal anxiety) and 6.7 (6.0 to 8.0)/21 for the depression subscale (0, no depression, and 21, maximal depression). PASS estimates did not differ between the 2 populations. Conclusions Our study provides PASS estimates for 5 PROs commonly used in cLBP. Our estimates were stable between 2 independent populations of people with cLBP. The stability of our PASS estimates suggests that they are relevant for interpreting PRO values in clinical trials and practice. ClinicalTrials.gov no. (PREDID trial) NCT00804531 .

Objective Adipokines could be a link between metabolic syndrome (MS) and infertility. While the association between circulating adipokines and fertility has been extensively studied in females, this relationship in males was less investigated, although some adipokines are detectable in seminal plasma (SP). The aim of this study was to determine adipokine levels in blood and SP and to assess the relationships between adipokines, MS and semen parameters in men from infertile couples. Design Male partners of infertile couples referred to four medical French centers were enrolled in years 2013–2016. Methods Subjects (n = 160) aged 18–45 years were assessed for anthropometric, biochemical, sperm, and circulating hormonal parameters. Leptin, adiponectin, resistin, chemerin, visfatin, and IL-6 were measured in serum and SP. Results Infertility duration was higher in men with than without MS. Adipokine concentrations were higher in blood than in SP, except for IL-6 and visfatin. The most striking result was the significant correlation observed between seminal IL-6 and spermatozoid concentration, progressive motility, and sperm vitality. Moreover, while men with MS exhibited an expected lower adiponectinemia, they displayed 2.1-fold higher adiponectin levels in SP than men without MS. Finally, logistic regression analysis showed that BMI, infertility duration, and adiponectin serum/SP ratio were independently associated with MS. Conclusions These results suggest an involvement of seminal adipokines to modulate fertility in men with MS and that seminal IL-6 could play a beneficial role on sperm functionality. Further mechanistic studies are necessary to investigate the precise roles of these adipokines in male reproduction.

Objectives The objective of this study was to examine the impact of study characteristics on the score of the pragmatism/explanatory continuum of randomized controlled trials (RCTs) published in nursing journals using the PRagmatic Explanatory Continuum Indicator Summary (PRECIS)-2 tool. Study Design and Setting RCTs concerning five themes of nursing care indexed in the PubMed and CINAHL databases published from 2002 to 2005 and 2012 to 2015 were selected by title/abstract. A sample of 400 was randomly selected and evaluated with the PRECIS-2 tool and reading grid. Results The median PRECIS score was 32 of a possible 45 [28; 36] corresponding to a medium level of pragmatism. Studies with “medication” as an intervention had a more explanatory PRECIS score than studies with other intervention types (P = 0.015). Studies with “placebo” and “no usual care” as comparators had a more explanatory PRECIS score (P = 0.0027). The pragmatism/explanatory level was unaffected by impact factor (P = 0.42), h-index of the first and last author (P = 0.27 and P = 0.25, respectively), funding (P = 0.32), blinding (P = 0.41), sample size (P = 0.22), and time (P = 0.11). Conclusion This study highlights the pragmatism/explanatory level of nursing RCTs, the impact of the field of the article, and the comparator type on the pragmatism of these studies. Further studies are needed to confirm the astonishing result that blinding resulted in no significant difference in the PRECIS score.

Methicillin-resistant staphylococcal infections are a global burden. Area under the concentration-time curve to MIC (AUC/MIC) ratio is the pharmacokinetic (PK) parameter that best predicts vancomycin efficacy. Its therapeutic range is narrow, difficult to achieve because of a wide intersubject variability, especially in children, and is not routinely targeted since the AUC is rarely available. We investigated if an early Bayesian dose adjustment would increase the rate of vancomycin target attainment in the first 24 hours of treatment (H24) in children. We conducted a single-center randomized controlled trial in 4 pediatric departments of Necker-Enfants Malades Hospital (Paris, France). Patients aged 3 months to 17 years for whom intravenous vancomycin was started were eligible and randomized in a 1:1 ratio; routine care was compared with an early vancomycin therapeutic drug monitoring (3 h after treatment initiation) followed by an early Bayesian dose adjustment using a previously published population-based PK model that included age, body weight, and serum creatinine as covariates. The primary outcome was the proportion of patients of each group achieving vancomycin therapeutic range at H24, defined by AUC(0–24)/MIC of ≥400 and AUC(0–24) of ≤800 mg-h/liter. Ninety-nine patients were enrolled and 49 were randomized to the Bayesian group and 50 to the control group. Modified intention-to-treat analysis included 82 patients; 85% of Bayesian group patients achieved H24 vancomycin target versus 57% of control group patients (P = 0.007) with no difference regarding iatrogenic events. Early Bayesian dose adjustment increased the proportion of children achieving vancomycin target at H24, which may improve clinical outcomes of methicillin-resistant staphylococcal infections. (This study has been registered at ClinicalTrials.gov under identifier NCT02694458.)

Prednisone is an anti-inflammatory drug widely used in internal medicine and rheumatology, but dosing remains empirical. The active metabolite of prednisone is free prednisolone. The aim of this work was to build a population pharmacokinetic (PK) model that can predict free prednisolone concentrations in patients with inflammatory/immunologic conditions.A total of 107 patients from the department of internal medicine of Cochin hospital provided 343 observations. Blood samples drawn for biological analyses were used for drug determination. Total plasma prednisolone concentrations were measured by liquid chromatography-mass spectrometry, and the data were modelled using Monolix. The pharmacokinetics was ascribed a one-compartment open model with three transit compartments standing for the absorption and metabolism process. The model used predicts free concentrations that served to derive total concentrations given published binding constants. Only size parameters influenced the pharmacokinetics. Free prednisolone CLU /F and VU /F, scaled allometrically on lean body weight, were, respectively, 26.7 L/h and 94.3 L for 50 kg LBW. CLU /F interindividual variability was 0.20. The additive and proportional residual variabilities were, respectively, 4.3 µg/L and 0.20. The results point out some dosing issues, that is the possibility of under- or over-dosage in thin or overweight patients respectively.

Background Clinical relevance of commonly used patient-reported outcomes (PROs) is unclear in people with non-specific chronic low back pain (cLBP) (1). Objectives To estimate and compare patient acceptable symptom state (PASS) at 1 month post-intervention for 4 PROs between 2 populations of patients with non-specific cLBP and to determine which baseline variables contribute to having an acceptable symptom state at 1 month. Methods Overall, we included 256 patients: 135 patients with cLBP and active discopathy participated in a randomized controlled trial assessing the efficacy on pain at 1 month of a single glucocorticoid intradiscal injection compared to contrast alone (2), and 121 patients with cLBP and without active discopathy participated in a randomized controlled trial assessing the efficacy on pain at 4 months of 12 sessions of immersive virtual reality (VR) compared to usual care (3). Using an anchor-based method, PASS estimates for PROs were obtained using the 75th percentile method (4). Logistic regression was used to determine baseline variables contributing to achieving PASS at 1 month. Results At 1 month, 137/256 (53.52%) participants self-rated their health as acceptable. In the whole population, PASS (95% IC) were 47.50 (40.00 to 50.00) for the lumbar-pain VAS, 30.50 (30.00 to 40.00) for the radicular-pain VAS, 39.27 (33.60 to 45.26) for the QUEBEC score, 9.95 (9.16 to 10.00) for the HAD anxiety subscale and 6.70 (6.00 to 8.00) for the HAD depression subscale. The PASS estimates did not differ between the 2 populations of cLBP patients for any of the PRO. The only baseline variable contributing to having an acceptable symptom state at 1 month was symptom intensity. Conclusion PASS estimates at 1 month did not vary across 2 independent samples of people with cLBP and 2 distinct nociceptive sources of cLBP. The main contributor of the PASS was symptom intensity at baseline. Our findings can be useful in interpreting the clinical relevance of PROs values. References [1] Tubach F, Ravaud P, Baron G, Falissard B, Logeart I, Bellamy N, et al. Evaluation of clinically relevant states in patient reported outcomes in knee and hip osteoarthritis: the patient acceptable symptom state. Ann Rheum Dis. 2005;64(1):34-7. [2] Nguyen C, Boutron I, Baron G, Sanchez K, Palazzo C, Benchimol R, et al. Intradiscal Glucocorticoid Injection for Patients With Chronic Low Back Pain Associated With Active Discopathy: A Randomized Trial. Ann Intern Med. 2017;166(8):547-56. [3] Nguyen C, Boutron I, Perrodeau E, Sanchez K, Borderie D, Palazzo C et al. 3D immersive virtual reality in patients with chronic low back pain: a randomized controlled trial. PlosOne (under review). 2017. Disclosure of Interests None declared

Background: Few patient-reported outcomes measures (PROs) have been specifically designed to assess the functioning of patients with systemic sclerosis (SSc). In addition, the development of currently available instruments did not fully follow current guidelines (1) Objectives: To develop and validate a PRO assessing activity limitation and participation restriction of patients with SSc. Methods: A provisional International Classification of Functioning, Disability and Health (ICF)-based 65-item questionnaire previously developed from interviews of SSc patients was submitted online to French patients (n=184) of the Scleroderma Patient-centered Intervention Network e-cohort (2). Items were reduced according to their metric properties, dimensional structure of the questionnaire was assessed by principal component analysis, convergent and divergent validities using the Spearman correlation coefficient (ρ), internal consistency by the Cronbach α coefficient and reliability by a test-retest method using intraclass correlation coefficient (ICC) and Bland and Altman analysis. Results: Overall, 113/184 (61.4%) patients completed the provisional questionnaire. The item-reduction process resulted in a 17-item questionnaire, the Cochin 17-item Scleroderma Functional scale (CSF-17). Principal component analysis extracted 2 dimensions: 10 items related to mobility (CSF-17 section A) and 7 items related to general tasks (CSF-17 section B). We observed convergent validity with global activity limitation, pain, depression and aesthetic burden and divergent validity with anxiety. The Cronbach α coefficient was 0.94 for section A and 0.95 for section B. ICC (n=25 patients) was 0.92 for CSF-17 total score. Bland and Altman analysis did not reveal a systematic trend for the test-retest. Conclusion: The CSF-17 is a self-administered questionnaire assessing activity limitation and participation restriction of patients SSc with good content and construct validities References [1] Health USDo, Human Services FDA, Research, et al. Guidance for industry: patient-reported outcome measures: use in medical product development to support labeling claims: draft guidance. Health Qual Life Outcomes. 2006;4:79. [2] Kwakkenbos L, Jewett LR, Baron M, Bartlett SJ, Furst D, Gottesman K, et al. The Scleroderma Patient-centered Intervention Network (SPIN) Cohort: protocol for a cohort multiple randomised controlled trial (cmRCT) design to support trials of psychosocial and rehabilitation interventions in a rare disease context. BMJ Open. 2013;3(8). Acknowledgement: Dr Camille Daste received a Master 2 grant from the French Society of Rheumatology Disclosure of Interests: None declared

International audience; Self-assessment of disease activity is feasible in rheumatoid arthritis, but its frequency decreases over time.

Purpose Registered nurses must have a level of scientific literacy to be able to interpret research data and access Scientific's knowledge. Several studies have been conducted to explore barriers and levers to the dissemination of nurse's knowledge; however, the scientific literacy that nursing students acquire has not been studied. Objective The aim was to examine and compare the way that research is taught to undergraduate nursing students in France and other countries. Design Cross-sectional, Internet survey. Settings Universities providing undergraduate nursing programs around the world. Participants Nurses educators. Methods Schools of nursing and universities were contacted by mail, through social networks and with the help of national or international nursing organizations. Respondents provided demographic data on schools and faculties of nursing, the teaching of scientific databases, Reading Critical Analysis and the teaching of scientific English. Information on the transmission of articles and access to scientific knowledge by students through the institution were also requested. Findings A total of 245 nursing schools/universities participated. Most respondents were educational research referees (52.2%), worked in a public institution (85.7%) and were in the nursing program leading to a bachelor's degree (74.3%). Databases were taught at 56.8%, Critical Reading of Articles at 70.1%, scientific English at 60.6% of nursing schools or universities. Articles were provided to students at 89.6% of institution and students had access to data through the institution in 66.1% of nursing schools or universities. Several significant differences were found between French schools of nursing and nursing schools/universities in other countries. Conclusions Our results show that most schools or universities of nursing teach the three majors' components to promote, provide articles to students and give access to scientific knowledge. However, there is wide heterogeneity between countries. There is a need to standardize research education for nursing students worldwide to promote the development of scientific literacy skills.

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.

Background Nursing care should be based on scientific evidence. However, studies must be performed rigorously with accurate reporting for their findings to be applicable to practice. Since the body of scientific nursing literature is broad, the quality and validity of its findings should be regularly controlled and verified to ensure their application and their practical impact. Purpose To compare reporting quality of pediatric randomized controlled trial (RCT) articles in nursing and medical journals. Methods Randomly selected articles were reviewed and scored to assess the number of CONSORT items that were adequately reported, generating a CONSORT score. The CONSORT scores for 28 items were compared between the two journal types. Results and discussion The CONSORT scores by journal type were not significantly different: (19.2 [16.2; 22] for medical journals and 19.5 [16.1; 21.5] for nursing journals, p = .77). The reporting of CONSORT items was poor for both journal types. However, there were two significant differences: item 19 (Declaration of all important harm or unintended effects, p = .0006) and item 23 (Registration number of the study, p = .0003), were reported more often in medical journals. The adherence of journals to the CONSORT statement and large sample size was associated with better quality of the reporting of studies. Conclusions Based on reporting quality, nursing studies have the same scientific credibility and rigor as medical studies in the pediatric field. Linking evidence to action The findings of this study could help researchers improve the reporting of their studies and highlight the importance of reporting quality for future knowledge transfer and practical use. The quality of research and its reporting is necessary to improve knowledge transfer into practice.

Aims Pregnant women can be exposed to numerous drugs during the gestational period. For obvious ethical reasons, in vivo studies of fetal exposure to drugs are limited. Information about the transplacental transfer of drugs prior to their administration to pregnant women would be highly useful. In the present study, a novel approach was developed quantitatively predict or to predict the fetal exposure to drugs administered to the mother quantitatively. Methods Transplacental parameters estimated from ex vivo human placenta perfusion experiments were implemented in pregnancy-physiologically based pharmacokinetic (p-PBPK) models in order to predict fetal PK. Thereafter, fetal PK profiles for two antiretroviral drugs, tenofovir (TFV) and emtricitabine (FTC) were simulated. These predictions were then compared to observed cord blood concentrations, to validate these models. Results Parameters obtained from the ex vivo experiments enabled a good prediction of observed cord blood concentrations without additional a scaling factor. Moreover, a sensitivity analysis showed that fetal predictions were sensitive to changes in transplacental parameters values obtained ex vivo. Conclusion The integration of ex vivo human placental perfusion parameters in a p-PBPK model should be a promising new approach for predicting human fetal exposure to xenobiotics.

Aim Physiological changes during pregnancy can affect drug disposition. Anticipating these changes will help to maximize drug efficacy and safety in pregnant women. Our objective was to determine if physiologically-based pharmacokinetics (PBPK) can accurately predict changes in the disposition of renally excreted antiretroviral drugs during pregnancy. Methods Whole body PBPK models were developed for three renally excreted antiretroviral drugs, tenofovir (TFV), emtricitabine (FTC) and lamivudine (3TC). To assess the impact of pregnancy on PK, time-varying pregnancy-related physiological parameters available within the p-PBPK Simcyp® software package were used. Renal clearance during pregnancy followed glomerular filtration changes with or without alterations in secretion. PK profiles were simulated and compared with observed data, i.e. area under the curves (AUC), peak plasma concentrations (Cmax) and oral clearances (CL/F). Results PBPK models successfully predicted TFV, FTC and 3TC disposition for non-pregnant and pregnant populations. Both renal secretion and filtration changed during pregnancy. Changes in renal clearance secretion were related to changes in renal plasma flow. The maximum clearance increases were approximately 30% (TFV 33%, FTC 31%, 3TC 29%). Conclusions Pregnancy PBPK models are useful tools to quantify a priori the drug exposure changes during pregnancy for renally excreted drugs. These models can be applied to evaluate alternative dosing regimens to optimize drug therapy during pregnancy.

ObjectiveAs the results from epidemiological studies about the impact of outdoor air pollution on asthma in children are heterogeneous, our objective was to investigate the association between asthma exacerbation in children and exposure to air pollutants.MethodsA database of 1 264 585 paediatric visits during the 2010–2015 period to the emergency rooms from 20 emergency departments (EDs) of ‘Assistance Publique Hôpitaux de Paris (APHP)’, the largest hospital group in Europe, was used. A total of 47 107 visits were classified as asthma exacerbations. Concentration of air pollutants (nitrogen dioxide, ozone, fine particulate matter (PM) with an aerodynamic diameter smaller than 10 µm (PM10) and 2.5 µm (PM2.5)), as well as meteorological data, evolution of respiratory syncytial virus infection and pollen exposition, were collected on an hourly or daily basis for the same period using institutional databases. To assess the association between air pollution and asthma, mixed-effects quasi-Poisson regression modelling was performed.ResultsThe only compound independently associated with ED visits for asthma was PM2.5 (P−4). The association between asthma exacerbation and PM2.5 was not linear, and a sigmoid function described the relationshipsatisfactorily. PM2.5 concentration, which gives half the maximum effect, was estimated at 13.5 µg/m3.ConclusionsWe found an association between daily asthma exacerbation in paediatric visits to the ED and fine particulate air pollutants.

The MONOD ANRS 12206 trial was designated to assess simplification of a successful lopinavir (LPV)-based antiretroviral treatment in HIV-infected children younger than 3 years of age using efavirenz (EFV; 25 mg/kg of body weight/day) to preserve the class of protease inhibitors for children in that age group. In this substudy, EFV concentrations were measured to check the consistency of an EFV dose of 25 mg/kg and to compare it with the 2016 FDA recommended dose. Fifty-two children underwent blood sampling for pharmacokinetic study at 6 months and 12 months after switching to EFV. We applied a Bayesian approach to derive EFV pharmacokinetic parameters using the nonlinear mixed-effect modeling (NONMEM) program. The proportion of midinterval concentrations 12 h after drug intake (C12 h) corresponding to the EFV therapeutic pharmacokinetic thresholds (1 to 4 mg/liter) was assessed according to different dose regimens (25 mg/kg in the MONOD study versus the 2016 FDA recommended dose). With both the 25 mg/kg/day dose and the 2016 FDA recommended EFV dose, simulations showed that the majority ofC12 hvalues were within the therapeutic range (62.6% versus 62.8%). However, there were more children underexposed with the 2016 FDA recommended dose (11.6% versus 1.2%). Conversely, there were more concentrations above the threshold of toxicity with the 25 mg/kg dose (36.2% versus 25.6%), withC12 hvalues of up to 15 mg/liter. Only 1 of 52 children was switched back to LPV because of persistent sleeping disorders, but hisC12 hvalue was within therapeutic ranges. A high EFV dose of 25 mg/kg per day in children under 3 years old achieved satisfactory therapeutic effective levels. However, the 2016 FDA recommended EFV dose appeared to provide more acceptable safe therapeutic profiles. (This study has been registered at ClinicalTrials.gov under identifier NCT01127204.)

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

To compare inter-reader concordance and accuracy of qualitative diffusion-weighted (DW) PIRADSv2.0 score with those of quantitative DW-MRI for the diagnosis of peripheral zone prostate cancer. Two radiologists independently assigned a DW-MRI-PIRADS score to 92 PZ-foci, in 74 patients (64.3±5.6 years old; median PSA level: 8 ng/ml, normal DRE in 70 men). A standardised ADCmean and nine ADC-derived parameters were measured, including ADCratios with the whole-prostate (WP-ADCratio) or the mirror-PZ (mirror-ADCratio) as reference areas. Surgical histology and MRI-TRUS fusion-biopsy were the reference for tumours and benign foci, respectively. Inter-reader agreement was assessed by the Cohen-kappa-coefficient and the intraclass correlation coefficient (ICC). Univariate-multivariate regressions determined the most predictive factor for cancer. Fifty lesions were malignant. Inter-reader concordance was fair for qualitative assessment, but excellent for quantitative assessment for all quantitative variables. At univariate analysis, ADCmean, WP-ADCratio and WL-ADCmean performed equally, but significantly better than the mirror-ADCratio (p

Aims The aims were to describe emtricitabine (FTC) pharmacokinetics in a large population of pregnant women during the different trimesters of pregnancy, and to explain FTC pharmacokinetic variability during pregnancy. Methods FTC plasma concentrations were measured in 103 non-pregnant and 83 pregnant women, including women in the different trimesters of pregnancy and on the day of delivery. A total of 457 plasma concentrations were available for analysis. A population pharmacokinetic model was developed with Monolix 4.1.3. Results FTC pharmacokinetics was best described by a two compartment model. The effect of creatinine clearance on apparent elimination clearance (CL/F) was significant. CL/F in pregnant women was significantly higher compared with non-pregnant women (geometric mean 24.1 vs 20.5 l h−1, P

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.

Aims To investigate 25-hydroxycholecalciferol [25(OH)D] population pharmacokinetics in children and adolescents, to establish factors that influence 25(OH)D pharmacokinetics and to assess different vitamin D3 dosing schemes to reach sufficient 25(OH)D concentrations (>30 ng ml−1). Methods This monocentric prospective study included 91 young HIV-infected patients aged 3 to 24 years. Patients received a 100 000 IU vitamin D3 supplementation. A total of 171 25(OH)D concentrations were used to perform a population pharmacokinetic analysis. Results At baseline 28% of patients had 25(OH)D concentrations below 10 ng ml−1, 69% between 10 and 30 ng ml−1 and 3% above 30 ng ml−1. 25(OH)D pharmacokinetics were best described by a one compartment model with an additional production parameter reflecting the input from diet and sun exposure. The effects of skin phototype and bodyweight were significant on 25(OH)D production before any supplementation. The basal level was 27% lower in non-white skin phototype patients and was slightly decreased with bodyweight. No significant differences in 25(OH)D concentrations were related to antiretroviral drugs. To obtain concentrations between 30 and 80 ng ml−1, patients with baseline concentrations between 10 and 30 ng ml−1 should receive 100 000 IU per 3 months. However, vitamin D deficient patients (

Aims This study aimed to describe lamivudine pharmacokinetics in patients with impaired renal function and to evaluate the consistency of current dosing recommendations. Methods A total of 244 patients, ranging in age from 18 to 79 years (median 40 years) and in bodyweight from 38 to 117 kg (median 71 kg), with 344 lamivudine plasma concentrations, were analysed using a population pharmacokinetic analysis. Serum creatinine clearance (CLCR) was calculated using the Cockcroft–Gault formula; 177 patients had normal renal function (CLCR > 90 ml min−1), 50 patients had mild renal impairment (CLCR = 60–90 ml min−1), 20 patients had moderate renal impairment (CLCR = 30–60 ml min−1), and five patients had severe renal impairment (CLCR < 30 ml min−1). Results A two-compartment model adequately described the data. Typical population estimates (percentage interindividual variability) of the apparent clearance (CL/F), central (Vc/F) and peripheral volumes of distribution (Vp/F), intercompartmental clearance (Q/F) and absorption rate constant (Ka) were 29.7 l h−1 (32%), 68.2 l, 114 l, 10.1 l h−1 (85%) and 1 h−1, respectively. Clearance increased significantly and gradually with CLCR. Our simulations showed that a dose of 300 mg day−1 in patients with mild renal impairment could overexpose them. A dose of 200 mg day−1 maintained an exposure close to that of adults with normal renal function. However, the current US Food and Drug Administration recommendations for lamivudine in other categories of patients (from severe to moderate renal impairment) provided optimal exposures. Conclusions Lamivudine elimination clearance is related to renal function. To provide optimal exposure, patients with mild renal impairment should receive 200 mg day−1 instead of 300 mg day−1.

Objectives The aims of this study were to analyze the viral load and CD4+ lymphocyte outcomes and the concentration-response of lopinavir/ritonavir (LPV/r) in the treatment of HIV-1-infected antiretroviral-naive children, to determine whether current dosing guidelines for LPV/r achieve Ctrough above 1.0 mg/L for naive patients to compare efficacy of World Health Organization 2010 and Food and Drug Administration dosing recommendations. Methods Clinical and biologic examinations were performed before treatment, 1 month, 3 months and then every 3 months in 47 antiretroviral-naive children who started an LPV/r-based regimen. LPV concentrations were also monitored on a routine basis, after 2 weeks of treatment initiation, between 1 and 24 hours after dosing in all children. A population pharmacokinetic-pharmacodynamic analysis was performed using an HIV dynamic model. Simulations of World Health Organization 2010 and Food and Drug Administration dosing recommendations were compared in terms of viral suppression. Results The HIV dynamic model adequately described the data. According to the concentration-effect curve, the LPV concentration providing 90% (CLPV90) and 95% (CLPV95) of effect were 1.2 and 2.4 mg/L, respectively. The World Health Organization 2010 guidelines should provide a higher probability of viral success, particularly in infants. Conclusions The CLPV90 derived from this model supports current dosing guidelines. However, the target of 2.4 mg/L corresponding to CLPV95 could be used to enhance the efficacy of this drug in treatment-naive children.

Background/purposeCardiovascular (CV) risk, cancer, infections and osteoporosis should be screened for in rheumatoid arthritis (RA). The objective was to assess 3-year effects of a nurse visit for comorbidity counselling.MethodsThis was an open long-term (3 years) extension of the Comorbidities and Education in Rheumatoid Arthritis 6-month randomised controlled trial in which patients with definite, stable RA were visiting a nurse for comorbidity counselling. Comorbidity status was assessed and nurses provided advice on screening and management, at baseline and 3 years later. A score was developed to quantify comorbidity screening and management: 0–100, where lower scores indicate better screening and management. The score was compared between baseline and 3-year assessment using a Wilcoxon test for paired data.ResultsOf the 970 recruited patients, 776 (80%) were followed-up at 2–4 years and 769 (79%) had available data for comorbidities at both time points: mean (±SD) age 58 (±11) years and mean disease duration 14 (±10) years; 614 (80%) were women, the mean Disease Activity Score 28 was 3.0±1.3, and 538 (70%) were receiving a biologic. At baseline, the mean comorbidity screening score was 36.6 (±19.9) and it improved at 3 years to 24.3 (±17.8) (pConclusionsComorbidity screening was suboptimal but improved notably over 3 years, after a nurse-led programme aiming at checking systematically for comorbidity screening and giving patient advice. This long-term efficacy pleads in favour of nurse-led interventions to better address comorbidities in RA.Trial registration numberNCT01315652

The aims of this study were to describe the pharmacokinetics of zidovudine (ZDV) and its biotransformation to its metabolite, 3*-azido-3*-deoxy-5*-glucuronylthymidine (G-ZDV), in HIV-infected children, to identify factors that influence the pharmacokinetics of ZDV, and to compare and evaluate the doses recommended by the World Health Organization (WHO) and the Food and Drug Administration (FDA). ZDV concentrations in 782 samples and G-ZDV concentrations in 554 samples from 247 children ranging in age from 0.5 to 18 years were retrospectively measured. A population pharmacokinetic model was developed with NONMEM software (version 6.2), and the pharmacokinetics of ZDV were best described by a one-compartment model with first-order absorption and elimination. The effect of body weight on the apparent elimination clearance and volume of distribution was significant. The mean population parameter estimates were as follows: absorption rate, 2.86 h −1 ; apparent elimination clearance, 89.7 liters · h −1 (between-subject variability, 0.701 liters · h −1 ); apparent volume of distribution, 229 liters (between-subject variability, 0.807 liters); metabolic formation rate constant, 12.6 h −1 (between-subject variability, 0.352 h −1 ); and elimination rate constant of G-ZDV, 2.27 h −1 . On the basis of simulations with FDA and WHO dosing recommendations, the probabilities of observing efficient exposures (doses resulting in exposures of between 3 and 5 mg/liter · h) with less adverse events (doses resulting in exposures below 8.4 mg/liter · h) were higher when the FDA recommendations than when the WHO recommendations were followed. In order to improve the FDA recommendations, ZDV doses should be reconsidered for the weight band (WB) of 20 to 40 kg. The most appropriate doses should be decreased from 9 to 8 mg/kg of body weight twice a day (BID) for the WB from 20 to 29.9 kg and from 300 to 250 mg BID for the WB from 30 to 39.9 kg. The highest dose, 300 mg BID, should be started from body weights of 40 kg.

Aims Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor used for chronic human immunodeficiency virus infections in adults and children. The aims of this study were to investigate the population pharmacokinetics of NVP in children, establish factors that influence NVP pharmacokinetics and evaluate the current dosing recommendations. Methods Concentrations were measured on a routine basis in 94 children aged from 2 months to 17 years. A total of 390 NVP plasma concentrations were retrospectively collected, and a population pharmacokinetic model was developed with Monolix 4.0. Results Nevirapine pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. After standardization to a 70 kg adult using allometry, postmenstrual age had a significant effect on the bioavailability. Estimates of apparent clearance and volume of distribution were 3.9 l h−1 (70 kg)−1 and 140 l (70 kg)−1, respectively. Based on simulations of European Medicines Agency (EMA) and World Health Organization (WHO) dosing recommendations, the probability of observing minimal concentrations below the efficacy target of 3 mg l−1 is higher following the EMA recommendations than the WHO recommendations. However, NVP underdosing persists for the 3–6 and 6–10 kg weight ranges following the WHO recommendations. Conclusions It is suggested to increase doses to 75 and 100 mg twice daily for the 3–6 and 6–10 kg weight ranges, respectively, in order to obtain more than 95% of children with concentrations above 3 mg l−1.