Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr): results from three multicentre, single-arm, phase 2 studies.

BACKGROUND: Rivaroxaban has been shown to be efficacious for treatment of venous thromboembolism in adults, and has a reduced risk of bleeding compared with standard anticoagulants. We aimed to develop paediatric rivaroxaban regimens for the treatment of venous thromboembolism in children and adolescents. METHODS: In this phase 2 programme, we did three studies to evaluate rivaroxaban treatment in children younger than 6 months, aged 6 months to 5 years, and aged 6-17 years. Our studies used a multicentre, single-arm design at 54 sites in Australia, Europe, Israel, Japan, and north America. We included children with objectively confirmed venous thromboembolism previously treated with low-molecular weight heparin, fondaparinux, or a vitamin K antagonist for at least 2 months or, in children who had catheter-related venous thromboembolism for at least 6 weeks. We administered rivaroxaban orally in a bodyweight-adjusted 20 mg-equivalent dose, based on physiologically-based pharmacokinetic modelling predictions and EINSTEIN-Jr phase 1 data in young adults, in either a once-daily (tablets; for those aged 6-17 years), twice-daily (in suspension; for those aged 6 months to 11 years), or three times-daily (in suspension; for those younger than 6 months) dosing regimen for 30 days (or 7 days for those younger than 6 months). The primary aim was to define rivaroxaban treatment regimens that match the target adult exposure range. The principal safety outcome was major bleeding and clinically relevant non-major bleeding. Analyses were per-protocol. The predefined efficacy outcomes were symptomatic recurrent venous thromboembolism, asymptomatic deterioration on repeat imaging at the end of the study treatment period. These trials are registered at ClinicalTrials.gov, numbers NCT02564718, NCT02309411, and NCT02234843. FINDINGS: Between Feb 11, 2013, and Dec 20, 2017, we enrolled 93 children (ten children younger than 6 months; 15 children aged 6 months to 1 year; 25 children aged 2-5 years; 32 children aged 6-11 years; and 11 children aged 12-17 years) into our study. 89 (96%) children completed study treatment (30 days of treatment, or 7 days in those younger than 6 months), and 93 (100%) children received at least one dose of study treatment and were evaluable for the primary endpoints. None of the children had a major bleed, and four (4%, 95% CI 1·2-10·6) of these children had a clinically relevant non-major bleed (three children aged 12-17 years with menorrhagia and one child aged 6-11 years with gingival bleeding). We found no symptomatic recurrent venous thromboembolism in any patients (0%, 0·0-3·9). 24 (32%) of 75 patients with repeat imaging had their thrombotic burden resolved, 43 (57%) patients improved, and eight (11%) patients were unchanged. No patient deteriorated. We confirmed therapeutic rivaroxaban exposures with once-daily dosing in children with bodyweights of at least 30 kg and with twice-daily dosing in children with bodyweights of at least 20 kg and less than 30 kg. Children with low bodyweights (<20 kg, particularly <12 kg) showed low exposures so, for future studies, rivaroxaban dosages were revised for these weight categories, to match the target adult exposure range. 61 (66%) of 93 children had adverse events during the study. Pyrexia was the most common adverse event (ten [11%] events), and anaemia and neutropenia or febrile neutropenia were the most frequent grade 3 or worse events (four [4%] events each). No children died or were discontinued from rivaroxaban because of adverse events. INTERPRETATION: Treatment with bodyweight-adjusted rivaroxaban appears to be safe in children. The treatment regimens that we confirmed in children with bodyweights of at least 20 kg and the revised treatment regimens that we predicted in those with bodyweights less than 20 kg will be evaluated in the EINSTEIN-Jr phase 3 trial in children with acute venous thromboembolism. FUNDING: Bayer AG, Janssen Research and Development.

Explaining the Muslim employment gap in Western Europe: individual-level effects and ethno-religious penalties.

It is well-documented that Muslims experience economic disadvantages in Western European labor markets. However, few studies comprehensively test individual-level explanations for the Muslim employment gap. Using data from the European Social Survey, this research note briefly examines the role of individual-level differences between Muslims and non-Muslims in mediating employment differences. Results reveal that human capital, migration background, religiosity, cultural values, and perceptions of discrimination jointly account for about 40% of the employment variance between Muslims and non-Muslims. Model specifications for first- and second-generation Muslim immigrants reveal a similar pattern, with migration background and perceived discrimination being of key relevance in mediating employment difference. While individual-level effects are indeed relevant, unexplained variance suggests that symbolic boundaries against Islam may still translate into tangible ethno-religious penalties.

The relation of mild traumatic brain injury to chronic lapses of attention.

We assessed the extent to which failures in sustained attention were associated with chronic mild traumatic brain injury (mTBI) deficits in cognitive control among college-age young adults with and without a history of sport-related concussion. Participants completed the ImPACT computer-based assessment and a modified flanker task. Results indicated that a history of mTBI, relative to healthy controls, was associated with inferior overall flanker task performance with a greater number of omission errors and more frequent sequentially occurring omission errors. Accordingly, these findings suggest that failures in the ability to maintain attentional vigilance may, in part, underlie mTBI-related cognition deficits.

Triple pelvic osteotomy in Legg-Calve-Perthes disease using a single anterolateral incision: a 4-year review.

Femoral head incongruency at skeletal maturity is associated with the development of osteoarthritis in early adulthood. Containment of the femoral head provides a larger surface area for remodelling of the collapsed femoral head and the development of spherical congruency. Triple pelvic osteotomy has a role to play in Legg-Calve-Perthes' disease by improving femoral head containment and preventing subluxation. This is traditionally a two-incision approach with significant associated morbidity. In our unit we perform triple osteotomies through a single anterolateral incision. To retrospectively review the clinical and radiographic outcome of children who had triple osteotomies performed through a single incision over a 4-year period. In our unit from 2003 to 2006 we performed eight triple osteotomies through a single incision in children aged between 6 and 12 years with Legg-Calve-Perthes' disease. The procedure was performed through a single anterolateral incision made beneath the middle of the iliac crest and carried forward according to Salter's osteotomy. Image intensification was used to confirm iliac, pubic and ischial cuts. After performing a standard Salter's osteotomy the acetabular fragment was free to rotate anteriorly and laterally. None of the children were casted and all were allowed immediate mobilization nonweight bearing with crutches for 6 weeks. Clinical results and hip function were measured preoperatively and postoperatively using the modified Harris hip score. The average length of hospital stay was 4.7 days. None of the children had a nonunion. The centre edge angle of Wiberg was measured on all preoperative and postoperative anteroposterior pelvic radiographs. In all our patients there was an improvement in the centre edge angle of Wiberg and in the modified Harris hip score. The preoperative modified Harris hip scores ranged from 38 to 60 and postoperatively ranged from 77 to 92. The preoperative centre edge angle of Wiberg ranged from 9 to 24 whereas postoperative scores ranged from 25 to 46. Triple osteotomy has been advocated in Legg-Calve-Perthes' disease after the closure of the triradiate cartilage. Using a single incision is a safer alternative to the traditional two-incision approach. We believe that the single incision approach reduces operative time and potential morbidity associated with the steel triple osteotomy with comparable clinical and radiographic outcomes.

Economic Outcomes among Latino Migrants to Spain and the United States: Differences by Source Region and Legal Status.

Using representative national surveys, this paper compares economic outcomes among Latin American migrants to Spain and the United States in the first cross-national comparison using quantitative data. Considering the geographic location and social proximity of each country with respect to Latin America, we detect a critical selection effect whereby the majority of Latin American migrants to Spain originate in South America from middle class backgrounds, whereas most migrants to the United States are Central Americans of lower class origins. This selection effect accounts for cross-national differences in the probability of employment, occupational attainment, and wages earned. Despite differences in the origins and characteristics of Latino immigrants to each country, demographic and human and social capital factors appear to operate similarly in both places; and when models are estimated separately by legal status, we find that effects are more accentuated for undocumented compared with documented migrants, especially in the United States.

The association between mild traumatic brain injury history and cognitive control.

The influence of multiple mild traumatic brain injuries (mTBIs) on neuroelectric and task performance indices of the cognitive control of action monitoring was assessed in individuals with and without a history of concussion. Participants completed a standard clinical neurocognitive assessment and the error-related negativity of the response-locked event-related brain potential and task performance were measured during a modified flanker task. The findings suggested that those individuals with a history of mTBI demonstrate certain failures in cognitive control, and indicated that a greater number of mTBIs may relate to poorer integrity in the evaluation or signaling for control during instances of conflict. Given that these neuroelectric and behavioral differences exist in the absence of disparities in standard clinical assessment, the findings suggest that measures of cognitive control may be more sensitive to signs of chronic cognitive dysfunction resulting from mTBI.

Isolated carpal scaphoid dislocation.

Isolated carpal scaphoid dislocations are rare. Because of this, treatment strategies can be conflicting and vague. The current authors present a case of isolated scaphoid dislocation that was treated initially with closed reduction and percutaneous pinning. Failure of this index treatment necessitated open reduction and internal fixation providing an adequate short-term outcome. Current treatment strategies now advocate ligament reconstruction as a first-line treatment to restore normal anatomy and preserve function.

Impact of dedicated skate parks on the severity and incidence of skateboard- and rollerblade-related pediatric fractures.

Dedicated skate parks have led to an increase in pediatric fractures referred to the authors' unit. The authors performed a prospective analysis of all patients presenting to their unit with fractures sustained while Rollerblading or skateboarding over a 5-month period. Epidemiologic data, user experience, wearing of protective gear, place of injury, and mechanism of injury were collected. Fracture type and its treatment were also recorded. The findings indicated that the use of skate parks is associated with a significant increase in the severity of fracture. This was not related to mean length of experience, age, or sex. The use of skate parks had an increased relative risk of 8.35 for fractures requiring manipulation or invasive orthopedic treatment. Only 5% of children were wearing some form of limb/joint protective gear. The authors believe there should be closer supervision and training of children and more emphasis on limb protective gear. The current high incidence of significant skate park injuries will otherwise continue, with implications for the well-being of these children and the burden on the healthcare system.