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INTRODUCTION: Genetic screening using high-throughput DNA sequencing has become a tool in diagnosing patients with suspected inherited bleeding disorders (IBD). However, its usefulness and diagnostic efficacy in children is unclear.AIM: To evaluate the diagnostic efficacy of genetic screening for IBD in children and downstream further testing.METHODS: After informed consent, children (

Many newly diagnosed Swedish severe haemophilia A (HA) patients are sporadic cases. Some genotypically non-carrier mothers have gone on to have two descendants with the same mutation, presumably due to mosaicism.

Haemophilia B is caused by a heterogeneous spectrum of mutations. Mutation characterization is important in genetic counselling, prenatal diagnosis and to predict risk of inhibitor development.To study the mutation spectrum, frequency of unique recurrent mutations, genotype-phenotype association and inhibitor development in a population-based study of the complete Swedish haemophilia B population.The study included, facilitated by centralized DNA diagnostics, the complete registered Swedish haemophilia B population (113 families: 47 severe, 22 moderate and 44 mild), each represented by a single patient. Mutation characterization was performed by conventional sequencing of all exons and haplotyping by genotyping of single nucleotide variants and microsatellites.A mutation was found in every family: eight had large deletions, three had small deletions (10 base pair) and 102 had single base pair substitutions (69 missense, 26 nonsense, four splice site and three promoter). Ten novel mutations were found and were predicted to be deleterious. Sixteen mutations (one total gene deletion, 14 substitutions and one acceptor splice site) were present in more than one family. Of the single nucleotide mutations (37/102), 36% arose at CpG sites. Haplotyping of families with identical mutations and present analyses showed that the frequency of unique mutations was at least 65%. Inhibitors developed in 9/47 (19%) patients with severe haemophilia B.The spectrum of haemophilia B mutations reveals at least 65% of the families carry a unique mutation, but with more inhibitor patients than reported internationally, probably as a result of many 'null' mutations.

The aims of the study were to define the frequency, outcome and reasons for prenatal diagnosis (PND) in Sweden during a 30-year period in order to study trends and changes. The study population, from the Swedish nationwide registry of PND of haemophilia, consisted of 54 women, compromising >95% of all, who underwent PND (n = 90) of haemophilia during 1977-2013. PND was performed by amniocentesis (n = 10), chorionic villus sampling (n = 64) or by analysis of foetal blood (n = 16). A total of 27/90 foetuses were found to have haemophilia. Sixteen went to termination and the remaining 11 were born during the end of the study period (2000-2013). Three of 90 pregnancies were terminated due to findings other than haemophilia and 3/90 PNDs led to miscarriage. In the 30 families with known haemophilia, PNDs (n = 55) were used in 27/55 cases for 'psychological preparation' and in 23/55 cases with the aim to terminate the pregnancy. A subgroup of women (n = 17) who consecutively underwent PND in the years 1997-2010 were further interviewed. For 11/17, being a carrier had a negative effect on the decision to become pregnant, and in 11 cases PND had influenced their decision to conceive. Our study show that PND of haemophilia is stable over time but increasingly used during the last decade as a psychological preparation for having a child with haemophilia as compared to earlier where more terminations of pregnancies were conducted.

In the current project, a finite element model is developed to analyse the long-term behaviour of timber beams. The time-dependent response of wood subjected to bending and moisture changes is investigated in terms of strains and stresses. A rheological model is implemented to capture the effects of creep, mechano-sorption and hygroexpansion. The model is validated against test results from Bengtsson and Kliger (Holzforschung 57:95–100, 2003). The results of the analysis showed that the mechano-sorptive creep of low- (LT) and high-temperature-dried (HT) timber beams can be sufficiently modelled with a spring and a single Kelvin body. The different mechano-sorptive behaviour of LT- and HT-dried specimens is considered with different mechano-sorptive and shrinkage–swelling parameters. The presented model could be used to derive general mechano-sorptive parameters: (1) for better prediction of creep over the service life and (2) to provide a basis of time-dependent probabilistic calculations for structural-sized timber in serviceability limit state.

Introduction Development of an inhibitor to Factor IX is a potentially life-threatening complication that occurs in 2-4% of severe hemophilia B patients. Attempt to eradicate these neutralizing alloantibodies with immune tolerance induction (ITI) regimens using prolonged repeated exposure to FIX fails to induce tolerance in ~70% of cases, and is limited by severe complications including FIX hypersensitivity and nephrotic syndrome. Cases of FIX ITI with immunosuppressive drugs have been reported infrequently. In light of increased understanding of the role of active T lymphocyte regulation of clotting factor-directed B lymphocyte-mediated humoral immunity, an approach combining immune modulating agents and frequent FIX infusions was reported by Beutel, et al (Haemostaseologie, 2009; 2014). We report a multi-institutional retrospective experience with combination immune modulation therapy (CIT), including B cell suppression with anti-CD20 monoclonal antibody Rituximab and T cell modulation using mycophenylate mofetil (MMF) with FIX ITI in 11 males with severe congenital hemophilia B. Methods The originally published regimen of Beutel, et al involves a 50 day course including FIX 100 IU/kg twice daily, rituximab 375 mg/m2 x 4 doses, mycophenolate (MMF) 300 mg/m2/dose daily, dexamethasone 6 mg/m2/dose pulses and IVIG 1 g/kg x 6 doses. Following individual Institutional Review Board approval, data on 11 patients was contributed by the INPH investigators and via outreach internationally and collected retrospectively using a uniform data collection form. Cases were included in the CIT series if the combination of FIX, rituximab and MMF was used. Approaches varied in the concomitant use of IVIG and pulse corticosteroids (dexamethasone or prednisone). Results CIT was the first immune tolerance therapy for 9/11 patients. Patients were 14-222 months of age at time of CIT, with a median time from inhibitor diagnosis to CIT 20 (range 0-207) months. Median historical peak inhibitor titer prior to initiation of CIT was 3.2 (range 1-42) BU/ml. Inhibitor titers at the initiation of CIT ranged from undetectable to 7 BU/ml. Eighty-onepercent of patients had a history of FIX hypersensitivity reaction. Prior to initiation of therapy, 27% of the patients underwent FIX desensitization during the initial course. The patients received FIX BID (9/11 patients) or QD (2/11 patients), 4 doses of rituximab 375 mg/m2, MMF for a minimum of 49 days (varying duration from 49-1247 days). IVIG was infused in 10/11 patients, with most receiving 3-7 doses during each course of CIT. 6/11 patients received between 2-10 courses of pulse corticosteroids during a CIT course. Each course of CIT achieved disappearance of the titer of FIX inhibitor at a median time of 1 month (range 1-41 months) Hypersensitivity reactions did not limit the courses of CIT, but did recur with inhibitor recurrence in 1 patient. Recurrence occurred in 6/11 patients at a median time of 11 months from time of CIT, in some cases soon after documented B cell recovery with a median inhibitor titer of 1.8 (range 0.7-7) BU/ml. In cases of recurrence, a negative inhibitor titer was achieved again in 1 patient by increasing FIX dose and in 4 patients who received additional courses of CIT. Repeat recurrence was seen in these patients following repeat CIT, although at low titer with a median of 1 BU/ml (range 1-4), allowing ongoing management with FIX in 3 of the 4. Overall, patients have had a median follow-up of 61 months following CIT, 9/11 patients are currently managed with factor IX for prophylaxis and bleeding, while 2/11 use bypassing agents. The most common complication was hospitalization for central venous catheter-related bacterial infection that occurred from < 1 to > 12 months after the use of rituximab in 3/11 patients. Nephrotic syndrome occurred in 3/11 patients. In each case, nephrotic syndrome responded to corticosteroids or re-initiation of CIT and FIX could be resumed. Conclusions FIX ITI with CIT targeting both B and T cells in hemophilia B is an effective means of achieving a negative inhibitor titer with tolerable safety in this series, allowing return to use of FIX for hemostasis and prophylaxis in most patients. Although recurrence is common and longer follow up is needed, when compared to the experience with using FIX alone, outcomes appear to be improved using CIT with FIX ITI as an initial approach. Disclosures Abajas: Bayer: Honoraria; CSL Limited: Honoraria. Allen:Shire: Employment, Equity Ownership. Oldenburg:Pfizer: Honoraria, Research Funding; Biogen: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Grifols: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Shire: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Swedish Orphan Biovitrum: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding.

To achieve a relatively consistent probability of failure for structural elements, most design codes apply reliability based code calibration process. Such approaches commonly focus on the strength of the structural members, which is related to the ultimate limit state (ULS). However in the design of beams the performance of the structural elements is often limited by the serviceability requirements, which are related to the serviceability limit state (SLS) using different load combinations than applied in the ultimate limit state. The current study aims to investigate the reliability for serviceability design for flexural members made of different materials (steel, concrete and timber) according to the specifications of the Eurocodes. Second-order reliability method (SORM) is applied to determine the reliability index for different design situations for beams subjected to bending. The probabilistic models of basic variables for time invariant analysis have been taken from the JCSS Probabilistic Model Code. The characteristic, the frequent and the quasi-permanent combination of actions are investigated and compared. The differences in service reliability for different materials are discussed. The results show that there are differences between the achieved reliability indices in the serviceability state between different materials and that for the given load combinations in the Eurocode the reliability index is often below the one given in the code. (C) 2011 Elsevier Ltd. All rights reserved. (Less)

Aims: To study the number, outcome and reasons for prenatal diagnosis (PND) and how it has affected the incidence of haemophilia, the number of siblings and the number of potential carriers in the families. Study Group: Women in SWE, compromising over 95% of total, who underwent PND of haemophilia during the years 1970-2010. A total of 46 women were identified who together underwent 79 PND procedures. Method: Structured personal interview and registry of laboratory analysis. So far, 27 women have been interviewed. Preliminary Results: 19/79 PND had been performed by analysis of foetal blood, 55/79 by genetic analysis of chorionic villi sampling and 5/79 by analysis of amniotic fluid. A total of 24 foetuses were found to be affected with haemophilia and 13/24 were aborted. The 24 foetuses affected with haemophilia were carried by 20 women. Twelve of these 20 women chose to end their pregnancy because of the findings. The preliminary results suggest that the drop in incidence of haemophilia due to PND in the 1990s no longer exists since almost half of the women today use PND to prepare themselves and their families psychologically to have a child with haemophilia and not to terminate the pregnancy. Furthermore, there seem to be more women becoming mothers since the improvement of care, thus giving birth to more children, both boys and girls, the latter being possible carriers. Conclusions: PND of haemophilia is still requested, but the number of affected foetuses aborted has diminished. Furthermore, the number of siblings seems to have increased, so the number of future carriers will also increase. (Less)

A number of rheological models of drying wood have been presented during the last ten years. At the material point level, most models show high accuracy. The models in themselves, however, have no value unless used for improving wood drying, technique, quality, etc. To achieve this, they have to be implemented in applicable programs/ methods. In this article, the implementation of a material model calibrated on small clear wood specimen is presented. The strain (cup-deformations) and the internal stresses (indicator of surface checks and internal collapse) of the boards cross-section are calculated for given moisture histories. Comparisons with test results concerning cupping show that the model can describe the deformation of a board cross-section. It is also shown that in many cases a simple analytical solution can be used to determine the cupping. Comparisons between two-dimensional and one-dimensional calculations show that the one-dimensional formulation in many cases is suf®cient to describe the maximum internal stresses during drying as function of time. (Less)

A constitutive model describing the stress-strain relations of wood under conditions of wood drying is compared against test results. A two-dimensional constitutive model is derived, valid for the behaviour perpendicular to grain. Analyses show that the mechano-sorption considerable reduces the stresses in a drying board. If wood was an elastic material without mechano-sorptive behaviour it would he impossible to dry timber. The two-dimensional model can be used in simulations of practical drying situations to estimate deformation of cross-section and asses the risk of checking.

A constitutive model describing the stress-strain relations of wood under conditions of wood drying is presented. The relations are valid for the behaviour perpendicular to grain in one dimension. The model is evaluated against test results. Analyses show that the mechano-sorptive effect in the tested material, Scots pine, is larger if restraint is imposed on the wood than if the load is constant. The model can be used in simulations of practical drying situations to estimate the risk of checking.

More than 1100 mutations that cause hemophilia B (HB) have been identified. At the same time, specific F9 mutations are present at high frequencies in certain populations, which raise questions about the origin of HB mutations.To describe the mutation spectrum of all HB families in Sweden and investigate if mutations appearing in several families are due to independent recurrent mutations (RMs) or to a common mutation event (i.e. are identical by descent (IBD)).The registered Swedish HB population consists of patients from 86 families. Mutations were identified by resequencing and identical haplotypes were defined using 74 markers and a control population of 285 individuals. The ages of IBD mutations were estimated using ESTIAGE.Out of 77 presumably unrelated patients with substitution mutations, 47 patients (61%) had mutations in common with other patients. Haplotyping of the 47 patients showed that 24 patients had IBD mutations (51%) with estimated ages of between two and 23 generations. A majority of these patients had mild disease. Eight of the 15 mutations observed in more than one family were CT transitions in CpG sites and all eight were RMs.The association of IBD mutations with a mild phenotype is similar to what has been previously observed in hemophilia A. Noteworthy features of the mutations that are common to more than one family are the equal proportions of patients with RM and IBD mutations and the correlation between the occurrence of RMs and CT transitions at CpG sites.

The effects on wood of simultaneous mechanical and moisture loading are studied. A constitutive model is given for the case of uniaxial stress in the longitudinal direction. The model has been quantified on the basis of test results found in literature. The validity of the model was checked independently against other tests and a number of practical load situations were studied. Finally the serviceablity requirements for design are discussed. The calculations show that the model is capable of describing the response of wood with reasonable accuracy. Some differences in behavior are found to depend on moisture cycling. The results of the simulations show that there is a significant influence of strain on the shrinkage and swelling response. An influence of beam dimensions has been found. The relative deflection for a small beam is larger than the deflection for a larger beam. Studies of the effect of varying load show that a temporarily applied load has little effect on the long-term deflection of structural timber. A simulation of snow-load variation shows that the long-term deflections are small in comparison with the case when the characteristic load is assumed to be constant over time. (Less)

A project concerning integrated computer-aided engineering systems in forest product industry has been carried out at Lund University, Sweden. Application programs which are parts of an integrated system have been developed, both programs based on AutoCAD and finite element analyzing programs. The work has been performed in cooperation with two factories, and contacts have also been taken with some presumptive customers to these factories. On the basis of a data base, computerized product catalogues have been developed. This paper describes the basic ideas in the project and some of the results are presented.

In a previous paper (Martensson 1988 a), results of tests performed on hardboard in tension under cyclic humidity were presented and comparison with a suggested constitutive model was made. This paper presents the result of further work that has been carried out concerning modelling of the behaviour of tempered hardboard subjected to moisture loading combined with mechanical loading. Tests were made both in compression and bending. The tests in compression were of two types, conventional creep tests during moisture cycling and quasi-relaxation tests during moisture cycling. The model was quantified on the basis of the previous tension tests and the compression tests, in both cases creep tests, and was then checked independently against the other types of test. Interaction between moisture change and mechanical loading was found to be significant during the first moisture cycle but much smaller during subsequent cycles. Experimental and numerical analysis of composite structural elements was also performed, showing that internal stresses of significant magnitude are developed as a result of variations in moisture. Such stresses can be predicted with reasonable accuracy using the proposed model. This can be of great value in design and development of wood products and wooden structural elements. (Less)

The effects on wood of simultaneous mechanical and moisture loading are studied. In order to clarify the mechano-sorptive behaviour of wood, a review of different phenomena presented in the literature is included. Based on this review a constitutive model is proposed for the case of uniaxial stress in the longitudinal direction. The validity of the model is checked independently against test results. The calculations show that the model is capable of describing the response of wood with reasonable accuracy. Simulations indicate that the response of small test specimens is more difficult to describe than that of larger beams. Some differences in behaviour are found to depend on loading mode and nature of moisture cycling. Very large and fast moisture cycles seem to give larger mechano-sorption than smaller variations. The results of the simulations show that there is a significant influence of strain on the shrinkage and swelling response.

Tests on tempered hardboard in tension were made with the purpose to study the effect of combined mechanical and moisture loading (mechano-sorption). The tests were performed both in a conventional way with constant load during the test period, and in quasirelaxation with the strain of each specimen prescribed during the test. In both cases the moisture content was varied. The tests show that the mechano-sorptive effects in the studied hardboard are small under constant load. In the relaxation tests the effects was found to be more significant. A constitutive model was suggested and quantified on the basis of test data from the constant load experiments. It was then checked independently against the other tests. The model was found to give good agreement with creep type experiments. When the model was checked against the relaxation type experiments, however, it showed poor agreement.