Thrombosis in Children

Aims: The general objective was to further elucidate thromboembolic disease in children and thereby help improve the care of these patients. More specific aims were as follows: to determine what children are affected by thrombosis; to discern any gender or age differences related to thrombosis; to identify prothrombotic risk factors; to ascertain whether autoantibodies against coagulation proteins constitute a risk factor for childhood thrombosis; to study girls receiving estrogen treatment with regard to induced hemostatic changes and efficacy of the therapy; to investigate long-term effects on the hemostatic system in children subjected to heart surgery. Material and methods: Children with thrombosis (Papers I and II) and children at risk of thrombosis (Papers III and IV) were investigated. In the initial study, 128 children referred for a first thrombotic event were retrospectively evaluated. In a subsequent endeavor, 57 children with thrombosis were prospectively included and evaluated for thrombotic risk factors, and patients and controls were investigated for autoantibodies. Considering children at risk, 63 girls treated with high doses of ethinyl estradiol were studied. Furthermore, 28 children with congenital heart defects were evaluated before and after Fontan surgery, and the results of follow-up global coagulation tests in patients and controls were analyzed. Results and conclusions: The present studies showed a bimodal age distribution in pediatric thrombosis patients in Sweden, with peaks in frequency rates during the neonatal period and in adolescence. The girls:boys ratio was 2:1. Of the children with thrombosis, 84% had acquired risk factors and they showed a significantly increased prevalence of inherited thrombophilia. Also, autoantibodies against prothrombin were significantly more often detected than in controls, suggesting immunological pathogenesis. Pediatric thrombosis often seem to be elicited by a combination of risk factors. Girls receiving high-dose estrogen treatment exhibited both pro- and anticoagulation abnormalities; the estrogen therapy was most effective when started at a younger bone age, and the risk of thrombosis was <5% and considered a safe treatment in our cohort. Post-Fontan patients had a lower incidence of procoagulant abnormalities at long-term follow-up compared to before surgery, although a subset of the subjects showed evidence of elevated thrombin generation, identified by increases in APC-PCI, as compared to controls. The results indicate that prophylaxis to prevent thrombosis in these children should be individualized

Effect of a spacer on total systemic and lung bioavailability in healthy volunteers and in vitro performance of the Symbicort\uae (budesonide/formoterol) pressurized metered dose inhaler

Introduction: Many patients with chronic obstructive pulmonary disease or asthma experience difficulties in coordinating inhalation with pressurized metered-dose inhaler (pMDI) actuation. The use of a spacer device can improve drug delivery in these patients. The aim of this study was to establish the relative bioavailability of single doses of Symbicort\uae (budesonide/formoterol) pMDI 160/4.5 μg/actuation (2 actuations) used with and without a spacer device. In addition, an in vitro study was conducted to characterize performance of the inhaler when used in conjunction with a spacer device. Methods: A Phase I, randomized, open-label, single-dose, single-center, crossover study in 50 healthy volunteers (NCT02934607) assessed the relative bioavailability of single-dose Symbicort\uae pMDI 160/4.5 μg/actuation (2 actuations) with and without a spacer (AeroChamber Plus\uae Flow-Vu\uae). Inhaled doses were administered without or with activated charcoal (taken orally) to estimate total systemic exposure and exposure through the lung, respectively. The in vitro study characterized the effect of the spacer with respect to delivered dose, fine particle dose, and dose during simulated breathing of budesonide and formoterol. Results: In terms of total systemic exposure, use of the spacer increased the relative bioavailability determined by AUC(0-last) and Cmax by 68% (spacer:no spacer treatment ratio, 167.9%; 90% CI, 144.1 to 195.6) and 99% (ratio, 198.7%; 90% CI, 164.4 to 240.2) for budesonide, and 77% (ratio, 176.6%; 90% CI, 145.1 to 215.0) and 124% (ratio, 223.6%; 90% CI, 189.9 to 263.3) for formoterol, respectively, compared with pMDI alone. Similarly, the lung exposure of budesonide and formoterol increased (AUC(0-last) and Cmax by 146% [ratio, 246.0%; 90% CI, 200.7 to 301.6] and 127% [ratio, 226.5%; 90% CI, 186.4 to 275.4] for budesonide, and 173% [ratio, 272.8%; 90% CI, 202.5 to 367.4] and 136% [ratio, 236.2%; 90% CI, 192.6 to 289.6] for formoterol, respectively) when the pMDI was administered through the spacer. When assessed by AUC(0-last) quartile without spacer, subjects in the lowest exposure quartile (indicating poor inhalation technique) with Symbicort\uae pMDI 160/4.5 μg/actuation (2 actuations) had markedly increased total systemic and lung exposure when the same dose was administered with the spacer. In contrast, for subjects in the highest exposure quartile with pMDI alone, total systemic and lung exposure of formoterol and budesonide was similar with and without the spacer. In the in vitro study, the fine particle dose (&lt;5 μm) of both budesonide and formoterol from the spacer at delay time (i.e. pause period after actuation) = 0 s (instantaneous) after actuation was similar to the fine particle dose when not using the spacer. The delivered doses of budesonide and formoterol from the spacer were both lower compared with the doses administered without the spacer. There was also a decrease in delivered dose with increasing delay time. Conclusions: The clinical study demonstrated that in subjects with poor inhalation technique the use of the AeroChamber Plus\uae Flow-Vu\uae spacer increased the bioavailability of Symbicort\uae pMDI to a level observed in subjects with good inhalation technique without a spacer. The findings from the in vitro study support the fine particle dose characteristics of Symbicort\uae pMDI with the AeroChamber Plus\uae Flow-Vu\uae spacer

Prospective registration of symptoms and times to diagnosis in children and adolescents with central nervous system tumors: A study of the Swedish Childhood Cancer Registry

Background: The elapsed time taken to diagnose tumors of the central nervous system in children and adolescents varies widely. The aim of the present study was to investigate such diagnostic time intervals at a national level in Sweden as they correlate with clinical features. Methods: Data prospectively accumulated over a 4-year period in the Swedish Childhood Cancer Registry from patients aged 0-18 years were pooled, and diagnostic time intervals were analyzed considering tumor location, tumor type, patient age and sex, initial symptoms, and clinical timelines. All six pediatric oncology centers in Sweden contributed to collection of data. Time points for calculating the total diagnostic interval (TDI) defined as the time from symptom onset to diagnosis were reported in 257 of 319 patients (81%). Results: The time from symptom onset to the first healthcare consultation, median 2.6 weeks, did not vary significantly between patients categorized according to tumor type or location. The median TDI was 8.3 weeks for the 4-year study period. Patients with optic pathway glioma (TDI 26.6 weeks), those with tumors of the spinal cord (TDI 25.9 weeks), and those with midline tumors (TDI 24.6 weeks) had the longest lead times. Additionally, older age, too few initial symptoms, and seeking initial redress outside an emergency ward were factors associated with a longer time to diagnosis. Conclusion: This study identified several factors associated with delayed diagnosis of central nervous system tumors among Swedish children and adolescents. These novel data ought to help direct future efforts toward clinical improvement.</p

Cerebellar mutism syndrome in children with brain tumours of the posterior fossa

Background: Central nervous system tumours constitute 25% of all childhood cancers; more than half are located in the posterior fossa and surgery is usually part of therapy. One of the most disabling late effects of posterior fossa tumour surgery is the cerebellar mutism syndrome (CMS) which has been reported in up to 39% of the patients but the exact incidence is uncertain since milder cases may be unrecognized. Recovery is usually incomplete. Reported risk factors are tumour type, midline location and brainstem involvement, but the exact aetiology, surgical and other risk factors, the clinical course and strategies for prevention and treatment are yet to be determined. Methods: This observational, prospective, multicentre study will include 500 children with posterior fossa tumours. It opened late 2014 with participation from 20 Nordic and Baltic centres. From 2016, five British centres and four Dutch centres will join with a total annual accrual of 130 patients. Three other major European centres are invited to join from 2016/17. Follow-up will run for 12 months after inclusion of the last patient. All patients are treated according to local practice. Clinical data are collected through standardized online registration at pre-determined time points pre- and postoperatively. Neurological status and speech functions are examined pre- operatively and postoperatively at 1-4 weeks, 2 and 12 months. Pre- and postoperative speech samples are recorded and analysed. Imaging will be reviewed centrally. Pathology is classified according to the 2007 WHO system. Germline DNA will be collected from all patients for associations between CMS characteristics and host genome variants including pathway profiles. Discussion: Through prospective and detailed collection of information on 1) differences in incidence and clinical course of CMS for different patient and tumour characteristics, 2) standardized surgical data and their association with CMS, 3) diversities and results of other therapeutic interventions, and 4) the role of host genome variants, we aim to achieve a better understanding of risk factors for and the clinical course of CMS - with the ultimate goal of defining strategies for prevention and treatment of this severely disabling condition.Peer reviewe

Distribution Channel Structure and Integration : Contingency variables in the sawmill industry

Purpose; The purpose of this paper is to identify and characterize structures and integration levels of distribution channels in the sawmill industry, as well as to discuss these characteristics and their association with different contingency variables. Design / methodology / approach; Multiple case study Findings: There is a variety of distribution channel structures and levels of integration in the sawmill industry: one extreme is small, one-unit firms delivering ex-works to export agents with unintegrated distribution channel processes and the other extreme is large, multi-unit firms with network flow structures delivering from their own stock on a market to clients with integrated distribution channel processes By studying these contingency variables, a pattern of sawmill categories emerges; the first category, in which production is focused, are the small single sawmills (with a cost leadership or focus strategy) which aim to deliver their products to independent actors ex-works; the sawmills which comply to this category do not consider logistics or IT as important, neither do they take integration into consideration. The second category consists of larger multi-unit sawmills with a downstream focus, which strive to integrate and control the distribution channel (in the most extreme cases acquire strategic actors) in order to achieve stable presence on strategic markets. Sawmills included in this category regard logistics and IT as important. Research limitations / implications; This research is an exploratory pre-study based on five case studies implicating a limited possibility to draw general conclusions. Practical implications: This paper illustrates situations in which the distribution channel requires to be focused to higher degree which is important for strategic decisions for the actors in the industry. What is original/value of paper: This paper illustrates the variety of channel structures and integration levels within a single industry, and connects the variation with a number of contingency variables