Alternative routes for tranexamic acid treatment in obstetric bleeding (WOMAN-PharmacoTXA trial): a randomised trial and pharmacological study in caesarean section births.

OBJECTIVE: To examine the safety, efficacy and pharmacology of intravenous (IV), intramuscular (IM) and oral tranexamic acid (TXA) use in pregnant women. DESIGN: Randomised, open-label trial. SETTING: Hospitals in Pakistan and Zambia. POPULATION: Women giving birth by caesarean section. METHODS: Women were randomised to receive 1 g IV, 1 g IM, 4 g oral TXA or no TXA. Adverse events in women and neonates were recorded. TXA concentration in whole blood was measured and the concentrations over time were examined with population pharmacokinetics. The relationship between drug exposure and D-dimer was explored. The trial registration is NCT04274335. MAIN OUTCOME MEASURES: Concentration of TXA in maternal blood. RESULTS: Of the 120 women included in the randomised safety study, there were no serious maternal or neonatal adverse events. TXA concentrations in 755 maternal blood and 87 cord blood samples were described by a two-compartment model with one effect compartment linked by rate transfer constants. Maximum maternal concentrations were 46.9, 21.6 and 18.1 mg/L for IV, IM and oral administration, respectively, and 9.5, 7.9 and 9.1 mg/L in the neonates. The TXA response was modelled as an inhibitory effect on the D-dimer production rate. The half-maximal inhibitory concentration (IC50 ) was 7.5 mg/L and was achieved after 2.6, 6.4 and 47 minutes with IV, IM and oral administration of TXA, respectively. CONCLUSIONS: Both IM and oral TXA are well tolerated. Oral TXA took about 1 hour to reach minimum therapeutic concentrations and would not be suitable for emergency treatment. Intramuscular TXA inhibits fibrinolysis within 10 minutes and may be a suitable alternative to IV

Population pharmacokinetics of lopinavir, atazanavir and nevirapine in children

Les pharmacocinétiques de deux inhibiteurs de protéase, le lopinavir et l'atazanavir et celle d'un inhibiteur non nucléosidique de la transcriptase inverse, la névirapine, ont été étudiées chez l'enfant par une approche de population. Cette approche nous a permis d'étudier les différentes sources de variabilité pharmacocinétique de chaque molécule antirétrovirale. La prise en compte des relations concentration-effet précédemment établies chez l'adulte, nous a permis, concernant l'atazanavir et la névirapine, de ré-évaluer les recommandations posologiques chez l'enfant en termes d'efficacité et de toxicité. L'étude réalisée sur le lopinavir/ritonavir nous a conduits à comparer en termes de pharmacocinétique, d'efficacité et de tolérance, le changement de rythme d'administration de deux prises à une unique prise par jour. Les résultats obtenus ont mis en évidence dans les trois études une augmentation de la clairance et du volume de distribution apparents en fonction du poids. Pour l'atazanavir, il a été montré que la co-administration de ritonavir ou de ténofovir résulte respectivement en une diminution ou augmentation de sa clairance apparente. Pour la névirapine, un effet de l'âge sur sa biodisponibilité a été mis en évidence, la biodisponibilité relative augmentant avec l'âge. En conclusion, le changement de rythme d'administration du lopinavir/ritonavir s'est avéré être équivalent sur le plan pharmacocinétique, mais a résulté en une baisse de la proportion de patients présentant une charge virale indétectable. Les recommandations posologiques actuelles d'atazanavir/ritonavir pourraient mener à un sur-dosage pour l'intervalle de poids 32-50 kg. Les doses de névirapine recommandées par l'Organisation Mondiale de la Santé pourraient mener à un sous-dosage pour les enfants pesant entre 3 et 10 kg.The pharmacokinetics of two protease inhibitors, lopinavir and atazanavir and that of a non-nucleoside reverse transcriptase inhibitors, nevirapine, has been studied in children by a population approach. This approach allowed us to study the factors affecting the pharmacokinetic variability of each antiretroviral drug. Based on adult concentration-effect relationships, we evaluated the recommended dosage of atazanavir and nevirapine in children in terms of efficacy and toxicity. The study of lopinavir led us to compare in terms of pharmacokinetics, efficacy and safety, a switch from the twice-daily to the once-daily lopinavir/ritonavir regimen. These three studies showed that the apparent clearance and the apparent volume of distribution increased allometrically with body weight. For atazanavir, it was shown that co-administration of ritonavir or tenofovir resulted respectively in a decrease or increase of its apparent clearance. For nevirapine, an effect of age on its bioavailability was pointed out, the relative bioavailability increased with age. In conclusion, the switch of lopinavir/ritonavir regimen was found to be to be equivalent in terms of pharmacokinetics, but resulted in a decrease in the proportion of patients with undetectable viral load. Current dosing recommendations for atazanavir/ritonavir may lead to over-dosage for the body weight range 32-50 kg. Doses of nevirapine recommended by the World Health Organization could lead to under-dosing for children weighing between 3 and 10 kg

System Simulation for EMC Network Analysis

International audienceThis paper uses compact models of power electronics converters to represent their EMC behavior. The model does not need any knowledge of the converter design since it is identified from external measurements. Three different DC-DC converters will be identified and the model validated in various network environment. Then, the models association in a DC network will be studied

Study characteristics impacted the pragmatism of randomized controlled trial published in nursing: a meta-epidemiological study

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Fine Particulate Pollution and Asthma Exacerbations

International audienceObjective : as 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.Methods : a 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.Results : the only compound independently associated with ED visits for asthma was PM2.5 (P<10−4). 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.Conclusions : we found an association between daily asthma exacerbation in paediatric visits to the ED and fine particulate air pollutants

Alendronate or Zoledronic acid do not impair wound healing after tooth extraction in postmenopausal women with osteoporosis

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

Identification and comparison of France to other countries of the teaching of research to nursing students: Results of an international survey of nursing educator

International audiencePurpose: 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

Pharmacokinetics and Virological Efficacy after Switch to Once-Daily Lopinavir-Ritonavir in Treatment-Experienced HIV-1-Infected Children▿

Lopinavir-ritonavir (LPV/r) is a protease inhibitor that is used twice daily (BID) in the treatment of HIV infection in children. In the context of a single-center observational study, a switch to a once-a-day (QD) LPV/r regimen was proposed for considerations of convenience and to support adherence. The aims of this study were to compare the pharmacokinetics, viral loads, percentages of CD4+ T cells, and lipid profiles after switching from a twice-daily to a once-daily regimen of LPV/r in experienced children. For this purpose, LPV concentrations, viral loads, CD4+ T cells, and biochemistry data were measured in routine therapeutic drug monitoring procedures in 45 children and adolescents. Thirty-six children were switched to the QD regimen. Nine children on the BID or QD regimen were added for pharmacokinetic-study purposes only. The QD trough concentrations (Ctrough) of lopinavir in plasma were significantly lower than those observed with the BID regimen (P < 0.0001), but the 24-h exposure levels were not significantly lower with the QD than with the BID regimen (P = 0.09). Among 34 evaluable patients who switched from the BID to the QD regimen, the virological efficacy of LPV/r appeared to differ (P < 0.001), with 74% and 57% of viral loads, respectively, being <50 copies/ml (mean follow-up times, 33 and 20 months). Among 22 patients with stable virological control before the switch, 12 experienced either failure or blip (one observation of detectable viral load between two observations of undetectable viral load) after the switch. The change from the BID to the QD regimen did not result in significant differences in CD4+ T cell percentages or total cholesterol, high-density lipoprotein (HDL) cholesterol, or triglyceride levels. The switch from the BID to the QD LPV/r regimen led to equivalent exposure and lower Ctrough values and resulted in lower levels of virological control in these antiretroviral-experienced children

Relationships between metabolic status, seminal adipokines, and reproductive functions in men from infertile couples

International audienceObjective 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

Pharmacokinetics of tranexamic acid after intravenous, intramuscular, and oral routes: a prospective, randomised, crossover trial in healthy volunteers.

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