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Background: Antithrombin [AT]-, protein C [PC]- or protein S [PS]-deficiency [D] constitutes a major risk factor for venous thromboembolism [VTE]. Primary study objective was to evaluate if the clinical presentation at first VTE onset differs between children and adults and to compare the individual recurrence risk among patients with respect to age at onset and their thrombophilia status ATD, PCD or PSD., Methods/patients/results: In 137 of 688 consecutively enrolled pediatric and adult VTE patients we calculated the absolute risk of VTE recurrence and event-free-survival adjusted for thrombophilia and positive family VTE history. At first VTE children manifested i) with a lower rate of pulmonary embolism, ii) a higher rate of cerebral vascular events or multiple VTEs, and iii) showed a higher proportion of unprovoked VTE compared to adolescents and adults. Adult patients reported more often a positive VTE history compared to younger study participants. The adjusted odds of recurrence in adults was 2.05 compared to children., Conclusion: At disease manifestation children and adults differ with respect to i) thrombotic locations, ii) percentage of unprovoked versus provoked VTE, and iii) different rates of positive VTE family histories. Furthermore, adults showed a two-fold increase risk of VTE recurrence compared to children., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Acquired hemophilia A (AHA) is caused by autoantibodies against factor VIII (FVIII). Immunosuppressive treatment (IST) results in remission of disease in 60% to 80% of patients over a period of days to months. IST is associated with frequent adverse events, including infections as a leading cause of death. Predictors of time to remission could help guide IST intensity but have not been established. We analyzed prognostic factors in 102 prospectively enrolled patients treated with a uniform IST protocol. Partial remission (PR; defined as no active bleeding, FVIII restored >50 IU/dL, hemostatic treatment stopped >24 hours) was achieved by 83% of patients after a median of 31 days (range 7-362). Patients with baseline FVIII <1 IU/dL achieved PR less often and later (77%, 43 days) than patients with ≥1 IU/dL (89%, 24 days). After adjustment for other baseline characteristics, low FVIII remained associated with a lower rate of PR (hazard ratio 0.52, 95% confidence interval 0.33-0.81, P < .01). In contrast, PR achieved on steroids alone within ≤21 days was more common in patients with FVIII ≥1 IU/dL and inhibitor concentration <20 BU/mL (odds ratio 11.2, P < .0001). Low FVIII was also associated with a lower rate of complete remission and decreased survival. In conclusion, presenting FVIII and inhibitor concentration are potentially useful to tailor IST in AHA., (© 2015 by The American Society of Hematology.)

Venous thromboembolism [TE] is a multifactorial disease and antithrombin deficiency [ATD] constitutes a major risk factor. In the present study the prevalence of ATD and the clinical presentation at TE onset in a cohort of paediatric index cases are reported. In 319 unselected paediatric patients (0.1-18 years) from 313 families, recruited between July 1996 and December 2013, a comprehensive thrombophilia screening was performed along with recording of anamnestic data. 21 of 319 paediatric patients (6.6%), corresponding to 16 of 313 families (5.1%), were AT-deficient with confirmed underlying AT gene mutations. Mean age at first TE onset was 14 years (range 0.1 to 17). Thrombotic locations were renal veins (n=2), cerebral veins (n=5), deep veins (DVT) of the leg (n=9), DVT & pulmonary embolism (n=4) and pelvic veins (n=1). ATD co-occurred with the factor-V-Leiden mutation in one and the prothrombin G20210A mutation in two children. In 57.2% of patients a concomitant risk factor for TE was identified, whereas 42.8% of patients developed TE spontaneously. A second TE event within primarily healthy siblings occurred in three of 313 families and a third event among siblings was observed in one family. In an unselected cohort of paediatric patients with symptomatic TE, the prevalence of ATD adjusted for family status was 5.1%. Given its clinical implication for patients and family members, thrombophilia testing should be performed and the benefit of medical or educational interventions should be evaluated in this high risk population.

Safety assessment is essential throughout medical product development. There has been increased awareness of the importance of safety trials recently, in part due to recent US Food and Drug Administration guidance related to thorough assessment of cardiovascular risk in the treatment of type 2 diabetes. Bayesian methods provide great promise for improving the conduct of safety trials. In this paper, the safety subteam of the Drug Information Association Bayesian Scientific Working Group evaluates challenges associated with current methods for designing and analyzing safety trials and provides an overview of several suggested Bayesian opportunities that may increase efficiency of safety trials along with relevant case examples., (Copyright © 2013 John Wiley & Sons, Ltd.)

Recently, consideration was given to the impact of dose selection strategies in phase IIb on the overall success of drug development programs. A natural next step is to simultaneously optimize design aspects of both phase IIB and phase III. We used type 2 diabetes as an example, including realistic regulatory and commercial scenarios for this indication. The expected net present value (eNPV) has been selected as the primary outcome because it naturally accommodates optimization, providing an explicit trade-off between the probability of success (PoS) and time delays and trial costs. Our findings are that larger studies and/or implementation of an adaptive design over a fixed design in phase IIb provide more precise dose selection and reduce the bias of treatment effects and uncertainty in the estimated eNPV within the range of sample sizes that we examined. Developers also have to ensure that dose selection criteria are consistent with development strategy and objectives.

Thromboses (VTE) in children were associated with medical diseases with and without acquired or inherited thrombophilic risk factors (IT). Disease recurrence rates vary between 3% in children with a first event during the neonatal period and 21% in children with idiopathic VTE. Recently reported systematic reviews showed significant associations between VTE and factor V G1691A or factor II G20210A mutations, protein C, protein S and antithrombin deficiency, more pronounced when combined IT were involved. The factor II G20210A mutation, protein C, protein S, and antithrombin deficiency did also play an important role at VTE recurrence. Primarily asymptomatic family members of pediatric VTE index cases showed annual VTE incidence rates of 2.82% in carriers of antithrombin, protein C, or protein S deficiency, 0.42% and 0.25% in carriers of the factor II G202010A or V G1691A mutation, and 0.10% in relatives with no IT., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: Previous studies in adults and mice have implicated ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), also known as von Willebrand factor (VWF)-cleaving protease, as a protective factor for stroke. Here we investigated ADAMTS13 in 208 pediatric patients with arterial ischemic stroke (AIS) and 125 population-based control children in a frequency-matched case-control study., Methods: The proportion of patients/controls with ADAMTS13 activity levels below and above the 10th percentile was compared. Additionally, in a quintile comparison, the proportion of patients versus controls in the lowest ADAMTS13 quintile was compared to those in the 2nd to 5th quintiles. Adjustment was performed for VWF antigen (VWF:Ag), factor VIII activity (FVIII:C), blood group, and age., Results: Forty-six of 208 patients (22%) showed ADAMTS13 levels below the 10th percentile, compared with 5 of 125 controls (4%; p < 0.001). Odds ratios/95% confidence intervals were 7.30/2.73-19.50 for the lowest percentile and 2.44/1.15-5.16 in the quintile comparison after adjustment for VWF:Ag, FVIII:C, blood group, and age. Comparing the proportion of patients with ADAMTS13 activity below the 10th percentile within the different stroke subtypes (undetermined, cardioembolic, steno-occlusive arteriopathies), no statistically significant differences were found (undetermined, 16 of 89; cardioembolic, 6 of 40; steno-occlusive arteriopathies, 24 of 79; p = 0.08). ADAMTS13 levels did not significantly differ among stroke subtypes (p = 0.29)., Interpretation: Our findings implicate reduced ADAMTS13 activity as a risk factor for pediatric AIS, and support the concept that ADAMTS13 has a role in the pathogenesis of pediatric AIS., (Copyright © 2012 American Neurological Association.)

Among the discussed risk factors for high-titre inhibitor (HRI) development in patients with hemophilia A (HA) are high dose FVIII replacement therapy and use of recombinant FVIII concentrates (rFVIII). The aim of this study was to evaluate the aforementioned risk factors for HRI development in children with hemophilia A ≤2%. About 288 ascertained PUPs (Israel and Germany) were followed after initial HA diagnosis over 200 exposure days. Inhibitor-free survival, hazard ratios (HR), and 95% confidence intervals (CIs) were calculated. Adjustment was performed for factor VIII concentrates, median single dose over the first three months of treatment, first FVIII administration before the age of three months, presence of risk HA gene mutations, "intensive treatment moments" and "year of birth" (proxy for different treatment periods). HRI occurred in 71/288 children (24.7%). In multivariate analysis adjusted for "year of birth", underlying risk gene mutations (HR/CI: 2.37/1.40-3.99), FVIII dose, measured per one IU increase per kgbw (HR/CI: 1.05/1.04-1.07), and first FVIII administration before the age of three months showed a significant impact on HR development. The risk of HRI development was similar for recombinant or plasmatic FVIII products. Children at risk should be treated with carefully calculated lower dose regimens, adapted to individual bleeding situations.

Pediatric stroke is a rare but highly penetrant disease with a strong genetic background. Although there are an increasing number of genome-wide association studies (GWASs) for stroke in adults, such studies for stroke of pediatric onset are lacking. Here we report the results of the first GWAS on pediatric stroke using a large cohort of 270 family-based trios. GWAS was performed using the Illumina 370 CNV single nucleotide polymorphisms array and analyzed using the transmission disequilibrium test as implemented in PLINK. An enrichment analysis was performed to identify additional true association signals among lower P value signals and searched for cumulatively associated genes within protein interaction data using dmGWAS. We observed clustering of association signals in 4 genes belonging to one family of metalloproteinases at high (ADAMTS12, P = 2.9 × 10(-6); ADAMTS2, P = 8.0 × 10(-6)) and moderate (ADAMTS13, P = 9.3 × 10(-4); ADAMTS17, P = 8.5 × 10(-4)) significance levels. Over-representation and gene-network analyses highlight the importance of the extracellular matrix in conjunction with members of the phosphoinositide and calcium signaling pathways in the susceptibility for pediatric stroke. Associated extracellular matrix components, such as ADAMTS proteins, in combination with misbalanced coagulation signals as unveiled by gene network analysis suggest a major role of postnatal vascular injury with subsequent thrombus formation as the leading cause of pediatric stroke.

Screening for inherited thrombophilia (IT) is controversial; persons at high risk for venous thromboembolism (VTE) who benefit from screening need to be identified. We tested 533 first- and second-degree relatives of 206 pediatric VTE patients for IT (antithrombin, protein C, protein S, factor V G1691A, factor II G20210A) and determined the incidence of symptomatic VTE relative to their IT status. The risk for VTE was significantly increased among family members with, versus without, IT (hazard ratio = 7.6; 95% confidence interval [CI], 4.0-14.5; P < .001) and highest among carriers of antithrombin, protein C, or protein S deficiency (hazard ratio = 25.7; 95% CI, 12.2-54.2; P < .001). Annual incidences of VTE were 2.82% (95% CI, 1.63%-4.80%) among family members found to be carriers of antithrombin, protein C, or protein S deficiency, 0.42% (0.12%-0.53%) for factor II G202010A, 0.25% (0.12%-0.53%) for factor V G1691A, and 0.10% (0.06%-0.17%) in relatives with no IT. Given the high absolute risk of VTE in relatives with protein C, protein S, and antithrombin deficiency, we suggest screening for these forms of hereditary thrombophilia in children with VTE and their relatives. Interventional studies are required to assess whether thromboembolism can be prevented in this high-risk population.

In neonates and infants with idiopathic venous thrombosis (VTE) and in pediatric populations in which thromboses were associated with medical diseases, inherited thrombophilia (IT) have been described as risk factors. Follow-up data for VTE recurrence in neonates suggest a recurrence rate between 3% in provoked and 21% in idiopathic VTE. Apart from underlying medical conditions, recently reported systematic reviews on pediatric VTE have shown significant associations between factor V G1691A, factor II G20210A, and deficiencies of protein C, protein S and antithrombin, even more pronounced when combined IT were involved. Independent from the age at first VTE onset, the pooled odds ratios (OR: single IT) for VTE ranged from 2.4 for the factor II G20210A mutation to 9.4 in neonates and infants with antithrombin deficiency. The pooled OR for persistent antiphospholipid antibodies/lupus anticoagulants was 4.9 for pediatric patients with venous VTE. The factor II G20210A mutation (OR: 2.1), and deficiencies of protein C (OR: 2.4), S (OR: 3.1) and antithrombin (OR: 3.0) also played a significant role at recurrence. Based on these data, screening and treatment algorithms must be discussed., (Copyright © 2011. Published by Elsevier Ltd.)

Within the last two decades low molecular weight heparins (LMWH) have gained increasing widespread use as anticoagulants in children. The use of LMWH has been implemented into clinical care even though there is a lack of firm evidence on the efficacy and safety of LMWH in this population due to the absence of sufficiently powered randomized controlled trials. In the absence of clinical trials, we performed a meta-analysis of available single-arm studies using LMWH in children. A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1980 to 2010 was conducted using keywords in combination both as MeSH terms and text words. Two authors independently screened citations and those meeting a priori defined inclusion criteria were retained. Data on year of publication, study design, country of origin, number of patients, ethnicity, venous thromboembolic events type, and frequency of recurrence and major bleedings were abstracted. Pooled incidence rates (IR) including 95% confidence intervals (95% CIs) on efficacy and safety data of LMWH administration on primary prophylaxis, as well as on secondary prophylaxis in children following symptomatic thromboembolism (TE) were shown. We included 2251 pediatric patients derived from 35 single-arm studies from 12 study countries who were eligible for analysis in the present systematic review. Pooled incidence rates (95% CI) to develop first TE on primary prophylaxis, further TE event on LMWH secondary prophylaxis, or a major bleeding event on LMWH were 0.047 (0.023 to 0.091), 0.052 (0.037 to 0.073) for efficacy, and 0.054 (0.039 to 0.074) for safety (treatment data only), respectively. Efficacy and safety data are comparable with adult data. The present systematic review suggests that use of LMWH in children as primary prophylaxis and in treatment of symptomatic thrombosis is effective and safe. However, properly designed randomized controlled trials are needed., (© Thieme Medical Publishers.)

Objective: Limited data are available on health-related quality of life (HR-QoL) in pediatric stroke survivors. The aim of the present study was to assess HR-QoL by self-assessment and parent/proxy-assessment in children and adolescents who survived a first stroke episode., Methods: We investigated HR-QoL in pediatric stroke survivors (71 preschool children [G1] and 62 school children/adolescents [G2]) and in 169 healthy controls. HR-QoL was assessed in patients and parents/proxies with the generic KINDL-R questionnaire exploring overall well-being and 6 well-being subdimensions (physical, psychological, self-esteem, family-related, friend-related, and school-related). In pediatric stroke survivors the neurological long-term outcome was measured with the standardized Pediatric Stroke Outcome Measure., Results: Of stroke survivors, 65% exhibited at least 1 neurologic disability. Pediatric stroke survivors reported lower overall well-being compared with healthy controls. In G2 stroke patients, friend-related well-being respectively emotional well-being was significantly reduced compared with healthy controls (73.0 vs 85.0 points; p < 0.001 respectively 80.2 vs 84.5 points; p = 0.049). Parents/proxies of both stroke survivors rated the overall well-being and all subdimensions (except family-related and school-related well-being in G1 and G2 stroke survivors and physical functioning in G2 stroke survivors) lower compared with parents/proxies of healthy children/adolescents. Overall well-being was significantly reduced in children with moderate/severe neurological deficits compared with normal/mildly affected patients (75.5 vs 83.3 points, p = 0.01). Neonatal stroke survivors reported a significantly better neurological long-term outcome compared to childhood stroke survivors (82.0 vs 75.0 points; p = 0.005)., Interpretation: Pediatric stroke survivors compared with healthy controls are strongly affected regarding their overall well-being and older children/adolescents regarding their well-being with peers., (Copyright © 2011 American Neurological Association.)

In patients with von Willebrand disease (VWD) replacement therapy with factor VIII/von Willebrand (VWF) concentrates is increasingly applied as prophylactic regimen. Since 2000, 82 consecutively enrolled patients with clinically relevant bleeding episodes (spontaneous, peri- or postoperative) were diagnosed with VWD [type 1: 42/82; type 2: 24/82; type 3: 13/82; acquired: 3/82]. In all patients, decision for initiating prophylaxis was based on a bleeding score > 2 prior to diagnosis, concomitant with recurrent bleeds associated with anaemia in patients with on-demand VWD therapy. We report results on secondary prophylactic VWF replacement therapy applied in 32 patients [children n=13; adolescents n=7; adults n=12] with VWD [type 1: 4; type 2: 15; type 3: 13], 15 of which were females, and nine of these at the reproductive period. Eight patients were treated with Humate P® or Wilate® (n=24). Median [min-max] dose [vWF:RCo] was 40 [20-47] IU/kg, 23 patients were given substitution therapy twice weekly, seven patients three times a week, and two children four times per week. Within a 12-month-period haemoglobin concentrations returned to normal values. Median duration of prophylaxis was three years. Recurrent bleeding episodes stopped in 31 of 32 patients, whereas inhibitors developed in one. Following a 12-month observation period the monthly bleeding frequency and the bleeding score was significantly reduced [3 vs. 0.07; 3 vs. 0: p< 0.001], compared to the pre-prophylaxis/pre-diagnostic values. The use of secondary prophylactic VWF replacement therapy is an effective tolerated treatment modality, highly beneficial for patients with VWD, who present with recurrent bleeding events during on-demand therapy.

In recent years, Bayesian response-adaptive designs have been used to improve the efficiency of learning in dose-finding studies. Many current methods for analyzing the data at the time of the interim analysis only use the data from patients who have completed the study. Therefore, data collected at intermediate time points are not used for decision making in these studies. However, in some disease areas such as diabetes and obesity, patients may need to be studied for several weeks or months for a drug effect to emerge. Additionally, slow enrollment rates can limit the number of patients who complete the study in a given period of time. Consequently, at the time of an interim analysis, there may be only a small proportion (e.g., 20%) of patients who have completed the study. In this paper, we propose a new Bayesian prediction model to incorporate all the data (from patients who have completed the study and those who have not completed) to make decisions about the study at the interim analysis. Examples of decisions made at the interim analysis include adaptive treatment allocation, dropping nonefficacious dose arms, stopping the study for positive efficacy, and stopping the study for futility. The model is able to handle incomplete longitudinal data including missing data considered missing at random (MAR). A utility-function-based decision rule is also discussed. The benefit of our new method is demonstrated through trial simulations. Three scenarios are examined, and the simulation results demonstrate that this new method outperforms traditional design with the same sample size in each of these scenarios.

Object: The purpose of this study was to identify factors predictive of postoperative oculomotor nerve palsy among patients who undergo surgery for distal basilar artery (BA) aneurysms. The data can be used to estimate preoperative risk in this population. The natural history of oculomotor nerve palsy in patients with good outcomes is also defined., Methods: The cases of 163 patients with distal BA aneurysms, who were treated surgically between 1996 and 2002, were retrospectively studied to identify factors contributing to oculomotor nerve palsy. After the data had been collected, stepwise logistic regression procedures were used to determine the predictive effects of each variable on the development of oculomotor nerve palsy and to create a scoring system. Factors that interfered with resolution of oculomotor dysfunction in patients with good outcomes were also studied. Postoperative oculomotor nerve palsy occurred in 86 patients (52.8%) with distal BA aneurysms. The following factors were associated with postoperative oculomotor dysfunction, as determined by a categorical data analysis: (1) younger patient age (p < 0.001); (2) poor admission Hunt and Hess grade (p < 0.001); (3) use of temporary arterial occlusion (p < 0.001); 4) poor Glasgow Outcome Scale score (p < 0.001); and (5) the presence of a BA apex aneurysm that projected posteriorly (p < 0.001). For patients with good outcomes, postoperative oculomotor nerve palsy resolved completely within 3 months in 31 patients (52%) and within 6 months in 47 patients (80%). The projection of the BA aneurysm was associated with incomplete oculomotor recovery at 6 months postoperatively (p = 0.019)., Conclusions: The results of this study can help identify patients with a high risk for the development of oculomotor nerve palsy. This may help neurosurgeons in preoperative planning and discussions.

Objective: To identify factors predictive of postoperative lower cranial nerve palsy (LCNP) among patients undergoing surgery for vertebral artery (VA)- posteroinferior cerebellar artery (PICA) aneurysms. The natural history of this LCNP is defined, and its effect on postoperative patient course is analyzed. No similar study has been described in the literature., Methods: Fifty-two patients with VA-PICA aneurysms, who were treated surgically between 1996 and 2002, were retrospectively studied to identify factors contributing to postoperative LCNP. The effect of LCNP on intensive care unit stay and development of nosocomial pneumonia also was analyzed. All analyses were performed with Fisher's exact test., Results: Postoperative LCNP occurred in 25 patients (48.1%) with VA-PICA aneurysms. Of the factors investigated, the use of temporary or total occlusion was associated with increased incidence of postoperative LCNP (P <0.001). The average length of stay in the intensive care unit was 13.8 days for patients with LCNP defined as moderate to severe, compared with 7.92 days for patients with LCNP defined as none or mild (P=0.0014). Nosocomial pneumonia occurred only in patients with moderate to severe LCNP (P=0.022). Postoperative LCNP resolved completely within 3 months in 12 patients (48%) and within 6 months in 19 patients (76%) ., Conclusion: The results of this study can help to identify the effect and natural history of LCNP after surgical clipping of VA-PICA aneurysms. This information may assist neurosurgeons in expediting treatment, decrease the cost and length of hospital stays, and result in improved outcomes.

We describe improvements in and details for the construction, calibration and use of a device using a thermal conductivity cell for the measurement of low-level rates of water evaporation (E) from a small surface area. E is measured from 0.0 to 1.0 mg . min-1 with a correlation coefficient of 0.999 between measured and independently verified rates and amounts of water evaporation. Data are available as a recordable analog d.c. voltage as well as in digital display for E and for the amount of water evaporated during an operator defined time period. The device we describe is noninvasive and it is designed to be constructed of conventional components. It is useful not only for measuring transcutaneous water diffusion in normal and diseased skin, but also it is adequately sensitive and rapidly responding to follow thermoregulatory and psychogenic sweating in small (nom. 1.0 cm2) skin areas. It can also be used to measure accurately and precisely the rates at which water is adsorbed by and removed from inanimate materials, as well as to determine how much water they store.