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Rivaroxaban is approved in various regions for the treatment of acute venous thromboembolism (VTE) in children aged between 0 and 18 years and was recently investigated for thromboprophylaxis in children aged between 2 and 8 years (with body weights 30 kg) with congenital heart disease who had undergone the Fontan procedure. In the absence of clinical data, rivaroxaban doses for thromboprophylaxis in post-Fontan children aged 9 years and older or ≥30 kg were derived by a bridging approach that used physiologically-based pharmacokinetic (PBPK) and population pharmacokinetic (popPK) models based on pharmacokinetic (PK) data from 588 pediatric patients and from adult patients who received 10 mg once daily for thromboprophylaxis after major orthopedic surgeries as a reference. Both models showed a tendency toward underestimating rivaroxaban exposure in post-Fontan patients aged between 2 and 5 years but accurately described rivaroxaban PK in post-Fontan patients aged between 5 and 8 years. Under the assumption that hepatic function is not impaired in post-Fontan patients, PBPK and popPK simulations indicated that half of the rivaroxaban doses for the same body weight given to pediatric patients treated for acute VTE would yield in pediatric post-Fontan patients exposures similar to the exposure observed in adult patients receiving 10 mg rivaroxaban once daily for thromboprophylaxis. Simulation-derived doses (7.5 mg rivaroxaban once daily for body weights 30-50 kg and 10 mg once daily for body weights ≥50 kg) were therefore included in the recent US label of rivaroxaban for thromboprophylaxis in children aged 2 years and older with congenital heart disease who have undergone the Fontan procedure.

The MenACYW-TT conjugate vaccine is approved for prevention of invasive meningococcal disease (IMD) as a single dose in individuals ≥2 years of age in the United States and ≥12 months in EU and some other countries. This Phase II study evaluated the safety and immunogenicity of this vaccine and of concomitant pediatric vaccines in infants/toddlers (6 weeks-15 months of age).Five schedules of the MenACYW-TT conjugate vaccine were evaluated in the United States: 2, 4, 6, and 12 months; 2, 4, 6, and 15 months; 2, 4, and 12 months; 6 and 12 months; and 12 months alone. Routine pediatric vaccines (DTaP-IPV/Hib, PCV7/PCV13, MMR, and varicella) were administered per approved schedules. Proportions of participants with serum bactericidal antibodyassay with human complement (hSBA) titers ≥1:4 and ≥1:8, SBA with baby rabbit complement (rSBA) titers ≥1:8 and ≥1:128, and immune responses against concomitant vaccines were determined.Tenderness and irritability were the most frequent solicited injection site and systemic reactions. Similar proportions of participants achieved an hSBA titer ≥1:8 for all four serogroups regardless of whether 2 or 3 doses were administered in the first year of life. Following a second-year dose, 91-100% of participants achieved the threshold for all 4 serogroups in all schedules regardless of the number of doses in the first year of life. Similar responses were seen with rSBA. Immunogenicity and safety profile of concomitant vaccines was similar whether the MenACYW-TT conjugate vaccine was administered or not.MenACYW-TT conjugate vaccine administered with pediatric vaccines is safe and immunogenic regardless of the schedule and does not affect the immunogenicity or safety of the concomitant vaccines.NCT01049035.

MenACYW-TT is an investigational quadrivalent meningococcal conjugate vaccine intended for the prevention of invasive meningococcal disease (IMD) caused by serogroups A, C, W, and Y in individuals aged 6 weeks and above. This Phase II, randomized, open-label, multicenter, exploratory study assessed the safety and immunogenicity of MenACYW-TT compared with a quadrivalent meningococcal polysaccharide vaccine (MPSV4) in 301 healthy adults aged ≥56 y in the US (NCT01732627). Participants were randomized 2:1 to receive MenACYW-TT or MPSV4. Serum bactericidal assays using human (hSBA) or baby rabbit (rSBA) complement were used to measure functional antibodies against meningococcal serogroups A, C, W, and Y at baseline and 30 d post-vaccination. Safety data were collected up to 30 d post-vaccination. Proportions of study participants with hSBA titers ≥1:8 against serogroups A, C, W, and Y were increased at Day 30 compared with baseline in both vaccine groups. The proportions of participants with hSBA titers ≥1:8 after MenACYW-TT vaccination were comparable to those after MPSV4 vaccination for serogroups A and C (A: 93.8% vs. 85.1%; C: 74.9% vs. 62.8%) and distinctly higher than after MPSV4 for serogroups W and Y (W: 79.5% vs. 60.6%; Y: 80.5% vs. 59.6%). Proportions of participants with rSBA titers ≥1:8 were comparable between vaccine groups for all four serogroups. The reactogenicity profiles of both vaccines were similar. Most unsolicited adverse events (AEs) were of Grade 1 or Grade 2 intensity, and no serious AEs were reported. The MenACYW-TT conjugate vaccine was well tolerated and immunogenic in adults aged ≥56 y.

Background Patients with single‐ventricle physiology who undergo the Fontan procedure are at risk for thrombotic events associated with significant morbidity and mortality. The UNIVERSE Study evaluated the efficacy and safety of a novel liquid rivaroxaban formulation, using a body weight–adjusted dosing regimen, versus acetylsalicylic acid (ASA) in children post‐Fontan. Methods and Results The UNIVERSE Study was a randomized, multicenter, 2‐part, open‐label study of rivaroxaban, in children who had undergone a Fontan procedure, to evaluate its dosing regimen, safety, and efficacy. Part A was the single‐arm part of the study that determined the pharmacokinetics/pharmacodynamics and safety of rivaroxaban in 12 participants before proceeding to part B, whereby 100 participants were randomized 2:1 to open‐label rivaroxaban versus ASA. The study period was 12 months. A total of 112 participants were enrolled across 35 sites in 10 countries. In part B, for safety outcomes, major bleeding occurred in one participant on rivaroxaban (epistaxis that required transfusion). Clinically relevant nonmajor bleeding occurred in 6% of participants on rivaroxaban versus 9% on ASA. Trivial bleeding occurred in 33% of participants on rivaroxaban versus 35% on ASA. For efficacy outcomes, 1 participant on rivaroxaban in part B had a pulmonary embolism (2% overall event rate); and for ASA, 1 participant had ischemic stroke and 2 had venous thrombosis (9% overall event rate). Conclusions In this study, participants who received rivaroxaban for thromboprophylaxis had a similar safety profile and fewer thrombotic events, albeit not statistically significant, compared with those in the ASA group. Registration URL: https://www.clinicaltrials.gov . Identifier: NCT02846532.

Thrombosis remains an important complication for children with single ventricle physiology post-Fontan procedure and effective thromboprophylaxis is an important unmet medical need. To obviate conventional dose-finding studies and expedite clinical development, a rivaroxaban dose regimen for this indication was determined utilizing a model-informed drug development approach. A physiologically based pharmacokinetic (PBPK) rivaroxaban model was used to predict a pediatric dosing regimen that would produce drug exposures similar to that of 10 mg once daily in adults. This regimen was used in an open-label, multicenter Phase 3 study, which investigated the use of rivaroxaban for thromboprophylaxis in post-Fontan patients 2 to 8 years of age. The pharmacokinetics (PK) of rivaroxaban was assessed in Part A (n = 12) and in Part B (n = 64) of UNIVERSE. The safety and efficacy in the rivaroxaban group were compared to those in the acetylsalicylic acid group for 12 months. Pharmacodynamic endpoints were assessed in both parts of the study. Rivaroxaban exposures achieved in Part A and B were similar to the adult reference exposures. Prothrombin time also showed similarity to the adult reference. Exposure-response analysis did not identify a quantitative relationship between rivaroxaban exposures and efficacy/safety outcomes within the observed exposure ranges. A body-weight based dose regimen selected by PBPK modeling was shown in the UNIVERSE study to be appropriate for thromboprophylaxis in the post-Fontan pediatric population. Model-based dose selection can support pediatric drug development and bridge adult dose data to pediatrics, thereby obviating the need for dose-finding studies in pediatric programs. This article is protected by copyright. All rights reserved.

Background The Fontan procedure is the final step of the 3-stage palliative procedure commonly performed in children with single ventricle physiology. Thrombosis remains an important complication in children after this procedure. To date, guideline recommendations for the type and duration of thromboprophylaxis after Fontan surgery are mainly based on extrapolation of knowledge gained from adults at risk for thrombosis in other clinical settings. Warfarin is being used off-label, and because of its multiple interactions with other drugs and food, a new alternative is highly desirable. Rivaroxaban, a direct Factor Xa inhibitor with a predictable pharmacokinetic profile, is a candidate to address this medical need. Study design The UNIVERSE study is a prospective, open-label, active-controlled, multicenter study in children 2 to 8 years of age who have single ventricle physiology and had the Fontan procedure within the 4 months preceding enrollment. This study consists of 2 parts. In Part A, rivaroxaban pharmacokinetics, pharmacodynamics, safety, and tolerability are assessed to validate the pediatric dosing selected. In Part B, safety and efficacy of rivaroxaban versus acetylsalicylic acid are evaluated for thromboprophylaxis in children post–Fontan procedure. Children in each part will receive study drug for 12 months. Part A has been completed with 12 children enrolled. Enrollment into Part B is currently ongoing. Conclusions The UNIVERSE study aims to provide dosing, pharmacokinetics/pharmacodynamics, safety, and efficacy information on the use of rivaroxaban, an oral anticoagulant, versus acetylsalicylic acid, an antiplatelet agent, in children with single ventricle physiology after the Fontan procedure.

Children generally have a lower risk of venous thromboembolism (VTE) than adults, but those with acute and chronic conditions requiring hospitalization and surgical procedures are at increased risk. Anticoagulant use in children has not been systematically studied, and limited data exist. This study aimed to provide data on the conditions associated with use of anticoagulants, the type of anticoagulant used in children, and the incidence of thromboembolism and major bleeding events reported in this population.To increase understanding of the use of anticoagulant therapies in children with at-risk conditions, 3 health claims databases in the United States were analyzed to describe the characteristics of use of heparins, warfarin, and direct oral anticoagulants (DOACs). Cumulative drug exposure was determined for continuous exposure, defined as30 days. Unadjusted event rates of VTE and major bleeding after exposure to these therapies were reported. The data were presented descriptively and are not intended for comparison or to imply any causation.Anticoagulants were infrequently used in the pediatric population, including at any time point after Fontan surgery for congenital heart disease. Heparins were used most frequently in the population overall and especially for patients aged12 years. DOACs were used least often and primarily for patients ages 12 to18 years. Among pediatric patients exposed to anticoagulants, unadjusted incidence rates of VTE per 1000 person-years of exposure ranged from 30.8 to 34.0 for all DOACs, 21.6 to 46.2 for warfarin, and 6.0 to 7.3 for heparins. Rates per 1000 person-years for major bleeding ranged from 0 to 4.9 for all DOACs, 4.3 to 6.7 for warfarin, and 3.7 to 4.6 for heparins.With results from clinical trials evaluating DOACs in the pediatric population expected in the next 2 years, these descriptive real-world data may provide a baseline understanding of current prescribing patterns and outcomes associated with the use of DOACs and other anticoagulants in routine pediatric clinical practice. This information represents the use of real-world evidence and may function as the benchmark for evaluating changes in prescription practices and potential outcomes in the future.

Trace elements have been analysed in 23 tooth enamel and dentine samples from a Muslim population in Tauste (North Spain) to investigate health and palaeodietary patterns during the 8th–10th centuries. LA-ICP-MS technique was used to determine the chemical composition of teeth. Post-burial alteration was established by REE and U high content (1 > μg/g) and several samples, mainly of deciduous teeth, were discarded. Trace elements show different behaviour in dentine and enamel related to the composition of tissues. Five individuals had high Pb contents (ranging between 2 and 30 μg/g) suggesting intoxication by occupational exposure to anthropogenic lead. Considering the period of time, individual lead intoxication could be attributed to working activity. Young individuals vs adults, and males vs females show different food intake, probably due to sexual division of labour or social status. The palaeodietary pattern of the Tauste population provides insights into this Muslim community.

Children have historically been underrepresented or, indeed, omitted entirely, in drug trials, leading to a relative dearth of evidence in support of appropriate drug treatments for many pediatric diseases.[1][1], [2][2] Recent legislative initiatives in the United States and the European Union (EU

The Islamic necropolis discovered in Tauste (Zaragoza, Spain) is the only evidence that a large Muslim community lived in the area between the 8th and 10th centuries. A multi-isotope approach has been used to investigate the mobility and diet of this medieval Muslim population living in a shifting frontier region. Thirty-one individuals were analyzed to determine delta N-15, delta C-13, delta O-18 and Sr-87/Sr-86 composition. A combination of strontium and oxygen isotope analysis indicated that most individuals were of local origin although three females and two males were non-local. The non-local males would be from a warmer zone whereas two of the females would be from a more mountainous geographical region and the third from a geologically-different area. The extremely high delta(15) N baseline at Tauste was due to bedrock composition (gypsum and salt). High individual delta(15) N values were related to the manuring effect and consumption of fish. Adult males were the most privileged members of society in the medieval Muslim world and, as isotope data reflected, consumed more animal proteins than females and young males. Research Group GIU15/34 of the University of the Basque provided support to MO, XM, Country-UPV/EHU, http://www.ehu.eus/es/web/ikerkuntza. IT315-10 Research Group of the Basque Country Government provided support to IG LO MCZ, http://www.hezkuntza.ejgv.euskadi.eus/r43-5553/es/.

Drug abusers are generally more involved in crime, in particular property crime, than people who are not drug abusers. Substitution programs have been developed in order to improve drug users' quality of life and to decrease their criminal involvement. Several evaluations, but not all, have reported crime reductions following substitution therapies based on heroin and methadone prescription. This systematic review is aimed at gaining an overall picture on the respective effects of prescription of methadone vs. heroin and other substances. 66 studies were considered, and 46 were selected for inclusion in the review. They separately assess the impact of methadone, buprenorphine, heroin, naltrexone, dihydrocodeine or Levo alpha‐acetylmethadone substitution on the criminal behaviour of opiates addicts. Meta‐analytic techniques were used to identify overall effects of several substances. Heroin maintenance has been found to significantly reduce criminal involvement among treated subjects, and it is more effective in crime reduction than methadone maintenance. Methadone maintenance greatly reduces criminal involvement, but apparently not significantly more so than other interventions. Buprenorphine and Naltrexone have been found to be promising, although few studies have been identified using these substances in maintenance treatment. Executive Summary/Abstract BACKGROUND Drug abusers are generally more involved in crime, in particular property crime, than people who are not drug abusers. Substitution programs have been developed in order to improve drug users’ quality of life and to decrease their criminal involvement. Several evaluations, but not all, have reported crime reductions following substitution therapies based on heroin and methadone prescription. OBJECTIVES This systematic review is aimed at gaining an overall picture on the respective effects of prescription of methadone vs. heroin and other substances. Search strategy: Six databases (Medline, Campbell Crime and Justice Group, National Criminal Justice Reference Service, National Treatment Agency for Substance Misuse, JSTOR and Criminal Justice Abstracts) as well as relevant journals and websites (Harm reduction Journal, Journal of Substance Abuse Treatment, Drug and Alcohol Dependence, Drug and Alcohol Review, Drug and Therapeutics Bulletin, International Journal of Drug Policy, Journal of Clinical Psychopharmacology, Déviance et Société, Criminal Justice and Behavior, Criminologie, www.heroinstudie.de and www.drugscope.org.uk) have been searched for relevant studies meeting the inclusion criteria. SELECTION CRITERIA To be eligible, studies had to assess the effects of any substitution therapy (using e.g. methadone and/or opiates as substitution drugs). Only effects on offending have been considered. Comparisons of competing treatments (substitution therapy vs. any other form of treatment, including placebo treatment or no treatment at all) were restricted to studies meeting level 4 or higher on the scale developed by Sherman et al. (1997). In addition, one‐group pre‐post evaluations of substitution therapies were included because changes in offending are substantial compared to pre‐treatment levels, while comparisons of treatment with several substances often show modest differences. Finally, studies that assessed the impact of drug substitution at the macro (i.e. city or regional) level were also included. The three different types of studies have been analyzed separately. DATA COLLECTION AND ANALYSIS 66 studies were considered, and 46 were selected for inclusion in the review. They separately assess the impact of methadone, buprenorphine, heroin, naltrexone, dihydrocodeine or Levo‐alpha‐acetylmethadone substitution on the criminal behaviour of opiates addicts. Meta‐analytic techniques were used to identify overall effects of several substances. Comparisons of different treatments (i.e. substitution vs. any other treatment) were restricted to studies meeting levels 4 or 5 on the scale developed by Sherman et al. (1997). MAIN RESULTS Heroin maintenance reduces crime significantly more than Methadone maintenance. Methadone maintenance reduces offending more than treatments without substitution therapy, but the mean effect size is not significant (p >.1). However, very large (and significant) reductions in criminal behaviour are observed during methadone maintenance therapy with respect to pre‐treatment levels. Buprenorphine does not significantly reduce criminal behaviour, although effects are positive, be it with respect to methadone or a placebo. Naltrexone treatment reduces criminality significantly more than behaviour therapy or counselling. CONCLUSION Heroin maintenance has been found to significantly reduce criminal involvement among treated subjects, and it is more effective in crime reduction than methadone maintenance. Methadone maintenance greatly reduces criminal involvement, but apparently not significantly more so than other interventions. Buprenorphine and Naltrexone have been found to be promising, although few studies have been identified using these substances in maintenance treatment.

Immune responses to meningococcal conjugate (Menactra™; MCV-4) and plain polysaccharide (Menomune®-A/C/Y/W-135; PSV-4) vaccines against serogroups A, C, Y, and W-135 were assessed in 220 of 1037 Chilean children aged 2 to 10 years participating in a comparative safety trial. Both vaccines were generally well tolerated. Geometric mean serum bactericidal antibody (SBA) titers 28 days postvaccination were comparable in both groups for all four serogroups. Seroconversion was evident in >97% of MCV-4 and >90% of PSV-4 vaccinees who tested seronegative at baseline. Menactra™ safely induced broad and robust immune responses against serogroups A, C, Y, and W-135 in this population.

Quadrivalent meningococcal conjugate vaccine (Menactra [MenACWY-D]), was licensed in the United States in 2005 to prevent meningococcal disease in adolescents and adults. The license was extended to children aged 2-10 years in 2007 and extended again in 2011 to infants aged 9 months and older based, in part, on results from 3 phase III studies presented herein.The safety and immunogenicity of 2 doses of MenACWY-D was assessed in study-eligible children: dose 1 was administered at 9 months of age and dose 2 was administered 3 months later with or without routine childhood vaccines.Thirty days after vaccination, protective serum bactericidal assay-human complement titers ≥1:8 for meningococcal serogroups A, C, Y and W-135 were achieved by 86-100% of children receiving 2 doses of MenACWY-D. When MenACWY-D was concomitantly administered with measles, mumps, rubella and varicella or heptavalent pneumococcal conjugate vaccine, 81-98% of participants achieved protective responses (serum bactericidal assay-human complement titers ≥1:8 for all serogroups). All seroprotection rates were91% when the protective titer was defined as serum bactericidal assay-human complement ≥1:4. MenACWY-D did not interfere with measles, mumps, rubella or varicella vaccine responses (98-100% achieved protective titers). When heptavalent pneumococcal conjugate vaccine was given concomitantly with MenACWY-D, antipneumococcal antibody levels, although decreased, were protective for all serotypes by enzyme-linked immunosorbent assay (98-100% ≥ 0.35 μg/mL) and opsonophagocytic assay (99-100% ≥ 1:8). Adverse events were generally mild and similar across groups. Serious adverse events were uncommon.MenACWY-D was safe and immunogenic when given in 2 doses to infants and toddlers; this vaccine can be given with other common childhood immunizations.

To control vertical movements in the Orinoco Oil Belt, a high-precision levelling network was installed in an area of about 100 km2. Links to the National Geodetic Network were established. A total of 190 BMs with deep pile foundations is already installed and the first measurement campaign was concluded. The accuracies obtained are those of first-order levelling works.