Co-morbidities and bleeding in elderly patients with haemophilia-A survey of the German, Austrian and Swiss Society of Thrombosis and Haemostasis Research (GTH).

BACKGROUND: Nowadays patients with haemophilia survive longer due to improvements in haemophilia care. It has been hypothesized that the bleeding type and frequency may vary with age and are influenced by co-morbidities and co-medication in elderly patients. OBJECTIVES: To investigate a large group of patients older than 60 years of age with haemophilia concerning haemophilia treatment, bleeding pattern changes, co-morbidities, co-medication, bleeding sites and patient mortality. METHODS: A retrospective multi-centre data collection study was initiated on behalf of the German, Austrian and Swiss Society of Thrombosis and Haemostasis Research (GTH). Parameters of interest were investigated over the 5 years prior to study entry. RESULTS: A total of 185 haemophilia patients (mean age, 69.0±7.0 years, 29% with severe haemophilia) were included in the study. Regular prophylaxis was performed in 30% of the patients with severe haemophilia. In total, the annual bleeding rate was 2.49 and in patients with severe haemophilia 5.61, mostly caused by joint bleeds. Hypertension was the most common co-morbidity, but it occurred significantly less frequently than in an age-matched general population older than 70 years; 12% of the patients suffered from ischaemic heart disease, and 13% of the patients received anticoagulant or antiplatelet therapy. Within the observation period, 17% of the patients with severe haemophilia developed a higher frequency of bleeding symptoms, which was significantly associated with the use of antiplatelet or anticoagulant drugs. CONCLUSIONS: The most common co-morbidity of the patient population was hypertension, a considerable part had ischemic heart disease and antiplatelet or anticoagulant drugs.

European retrospective study of real-life haemophilia treatment.

INTRODUCTION: Haemophilia treatment varies significantly between individuals, countries and regions and details of bleed rates, factor consumption and injection frequency are often not available. AIM: To provide an overview of the FVIII/FIX treatment practice and outcome for patients with haemophilia A (HA) or haemophilia B (HB) across Europe. METHODS: Non-interventional, 12-month retrospective study where anonymized data were retrieved from haemophilia centres/registers in Belgium, France, Germany, Italy, Spain, Sweden and the United Kingdom. Male patients (all ages) receiving coagulation factor treatment 24 months prior to the study, with basal FVIII/FIX levels ≤5 IU dL-1 , without inhibitors, were included. Data were summarized descriptively. RESULTS: In total, 1346 patients with HA and 312 with HB were included in the analysis; 75% and 57% had severe disease (FVIII/FIX < 1 IU dL-1 ) respectively. Prophylaxis was most common for severe haemophilia, especially for children, whereas on-demand treatment was more common for moderate haemophilia in most countries. The mean (SD) prescribed prophylactic treatment ranged from 67.9 (30.4) to 108.4 (78.1) (HA) and 32.3 (10.2) to 97.7 (32.1) (HB) IU kg-1 per week, across countries. Most patients on prophylaxis were treated ≥3 times/week (HA) or two times/week (HB). The median annual bleeding rate (ABR) for patients on prophylaxis ranged from 1.0 to 4.0 for severe HA, and from 1.0 to 6.0 for severe HB, while those with moderate haemophilia generally had slightly higher ABRs. Median ABRs for on-demand-treated severe HA ranged from 4.5 to 18.0, and for HB, 1.5 to 14.0. CONCLUSION: Treatment practice varied greatly between centres and countries and patients treated on-demand and prophylactically both experienced bleeds, emphasizing the need for further optimization of care.

Diagnostic and prognostic value of factor VIII binding antibodies in acquired hemophilia A: data from the GTH-AH 01/2010 study.

UNLABELLED: Essentials Factor VIII (FVIII) binding IgG detected by ELISA could be an alternative to the Bethesda assay. We studied the performance of anti-FVIII IgG ELISA in patients with acquired hemophilia and controls. Anti-FVIII IgG > 99th percentile of controls was highly sensitive and specific. Patients with high anti-FVIII IgG have a lower chance of achieving remission. SUMMARY: Background Acquired hemophilia A is a severe bleeding disorder that requires fast and accurate diagnosis as it occurs often unexpectedly in previously healthy men and women of every age. The Nijmegen-modified Bethesda assay is the diagnostic reference standard for detecting neutralizing autoantibodies against factor VIII (FVIII), but is not widely available, not ideal for quantifying the complex type 2 inhibitors seen in acquired hemophilia, and suffers from high inter-laboratory variability. Objectives To assess the diagnostic and prognostic value of FVIII-binding antibodies as detected by ELISA compared with the Nijmegen Bethesda assay. Methods Samples from the time of first diagnosis and clinical data were available from 102 patients with acquired hemophilia enrolled in the prospective GTH-AH 01/2010 study. Controls (n = 102) were matched for gender and age. Diagnostic cut-offs were determined by receiver-operator curve analysis. The prognostic value was assessed in 92 of the 102 patients by Cox regression analysis of time to partial remission. Results Anti-FVIII IgG above the 99th percentile (> 15 arbitrary units per mL) revealed high sensitivity and specificity (both 0.99; 95% confidence interval, 0.95-1.0) for diagnosing acquired hemophilia. The likelihood of achieving partial remission was related to anti-FVIII IgG concentration (< 300 arbitrary units, 1.0; 300-1050, 0.65; > 1050, 0.39). The Bethesda titer was only associated with the likelihood of partial remission when analyzed in the central laboratory, but not when data from local GTH study sites were used. Conclusion Although the Nijmegen-modified Bethesda assay is the reference standard for demonstrating neutralizing antibodies, the detection of FVIII-binding antibodies by ELISA is similarly sensitive and specific for diagnosing acquired hemophilia. In addition, anti-FVIII IgG may provide prognostic information.

Integration of a model-independent interface for RBE predictions in a treatment planning system for active particle beam scanning.

Especially for heavier ions such as carbon ions, treatment planning systems (TPSs) for ion radiotherapy depend on models predicting the relative biological effectiveness (RBE) of the particles involved. Such models are subject to intensive research and the choice of the optimal RBE model is a matter of debate. On the other hand TPSs are often strongly coupled to particular RBE models and transition even to extended models of the same family can be difficult. We present here a model-independent interface which allows the unbiased use of any RBE model capable of providing dose-effect curves (even sampled curves) for a TPS. The full decoupling between the RBE model and TPS is based on the beam-mixing model proposed by Lam which is, in contrast to the often-used Zaider-Rossi model, independent of the explicit form of the underlying dose-effect curves. This approach not only supports the refinement of RBE models without adaptations of the TPS--which we demonstrate by means of the local effect model (LEM)--but also allows the comparison of very different model approaches on a common basis. We exemplify this by a comparison between the LEM and a model from the literature for proton RBE prediction.

Application of the local effect model to predict DNA double-strand break rejoining after photon and high-LET irradiation.

In the recent version of the local effect model (LEM), the biological effects of ionising radiation can be well described trough the consideration of DNA double-strand breaks (DSB) clustering at the micrometre scale. Assuming a giant-loop organisation for the chromatin higher-order structure, two classes of DSB are defined, namely isolated (iDSB) and clustered DSB (cDSB), according to whether exactly one or more than one DSB are induced in a loop, respectively. Here, a DSB kinetic rejoining model based on the LEM is applied to the description of two specific aspects of DSB rejoining, namely the dose dependence of the rejoining capacity after photon radiation and the residual damage observed at late times after ion irradiation. Based on the hypothesis that iDSB and cDSB can be associated to the fast and slow components of rejoining, the model is able to reproduce the experimental data, therefore supporting the relevance of micrometre scale clustering of damage for photon radiation as well as for high-LET radiation.

[Therapy of inherited diseases of platelet function. Interdisciplinary S2K guideline of the Permanent Paediatric Committee of the Society of Thrombosis and Haemostasis Research (GTH e. V.)]. / Therapie hereditärer Thrombozytopathien. Interdisziplinäre S2K-Leitlinie der Ständigen Kommission Pädiatrie der Gesellschaft für Thrombose- und Hämostaseforschung e. V.

Inherited disorders of platelet function are a heterogeneous group. For optimal prevention and management of bleeding, classification and diagnosis of the underlying defect are highly recommended. An interdisciplinary guideline for a diagnostic approach has been published (AWMF # 086-003 S2K; Hämostaseologie 2014; 34: 201-212). Underlying platelet disorder, platelet count, age and clinical situation modify treatment. Exclusive transfusion of platelet concentrates may be inappropriate as potentially adverse effects can outweigh its benefit. A stepwise and individually adjusted approach for restitution and maintenance of haemostasis is recommended. Administration of antifibrinolytics is generally endorsed, but is of particular use in Quebec disease. Restricted to older children, desmopressin is favourable in storage pool disease and unclassified platelet disorders. Although licensed only for patients with Glanzmann thrombasthenia and alloantibodies, in clinical practice rFVIIa is widely used in inherited platelet disorders with severe bleeding tendency. This guideline aims at presenting the best available advice for the management of patients with inherited platelet function disorders.

Clot waveform analysis in patients with haemophilia A.

UNLABELLED: Clot waveform analysis extends the interpretation of aPTT measurement curves. The curve is mathematically processed to obtain information about fibrin formation kinetics including semiquantitative determination of thrombin, prothrombinase and tenase activity. PATIENTS, METHOD: In this study the feasibility of clot waveform analysis for monitoring of haemophilia A was investigated using blood samples from healthy controls as well as haemophilia A patients under various clinical conditions. RESULTS: Thrombin, prothrombinase and tenase activity show a high correlation to factor VIII levels. Tenase activity was found to exhibit a linear relationship to factor VIII levels over a very large concentration range and was able to discriminate patients with severe, moderate and mild haemophilia. CONCLUSION: Clot waveform analysis is an easy, fast and cheap method to access disturbances in clot formation and can be done without any additional measurements beside an aPTT.

Kmasker--a tool for in silico prediction of single-copy FISH probes for the large-genome species Hordeum vulgare.

Specific localization of large genomic fragments by fluorescence in situ hybridization (FISH) is challenging in large- genome plant species due to the high content of repetitive sequences. We report the automated work flow (Kmasker) for in silico extraction of unique genomic sequences of large genomic fragments suitable for FISH in barley. This method can be widely used for the integration of genetic and cytogenetic maps in plants and other species with large and complex genomes if the probe sequence (e.g. BACs, sequence contigs) and a low coverage (8-fold) of unassembled sequences of the species of interest are available. Kmasker has been made publicly available as a web tool at http://webblast.ipk-gatersleben.de/kmasker.

A DNA double-strand break kinetic rejoining model based on the local effect model.

We report here on a DNA double-strand break (DSB) kinetic rejoining model applicable to a wide range of radiation qualities based on the DNA damage pattern predicted by the local effect model (LEM). In the LEM this pattern is derived from the SSB and DSB yields after photon irradiation in combination with an amorphous track structure approach. Together with the assumption of a giant-loop organization to describe the higher order chromatin structure this allows the definition of two different classes of DSB. These classes are defined by the level of clustering on a micrometer scale, i.e., "isolated DSB" (iDSB) are characterized by a single DSB in a giant loop and "clustered DSB" (cDSB) by two or more DSB in a loop. Clustered DSB are assumed to represent a more difficult challenge for the cell repair machinery compared to isolated DSB, and we thus hypothesize here that the fraction of isolated DSB can be identified with the fast component of rejoining, whereas clustered DSB are identified with the slow component of rejoining. The resulting predicted bi-exponential decay functions nicely reproduce the experimental curves of DSB rejoining over time obtained by means of gel electrophoresis elution techniques as reported by different labs, involving different cell types and a wide spectrum of radiation qualities. New experimental data are also presented aimed at investigating the effects of the same ion species accelerated at different energies. The results presented here further support the relevance of the proposed two classes of DSB as a basis for understanding cell response to ion irradiation. Importantly the density of DSB within DNA giant loops of around 2 Mbp size, i.e., on a micrometer scale, is identified as a key parameter for the description of radiation effectiveness.

Sensitivity analysis of the relative biological effectiveness predicted by the local effect model.

The relative biological effectiveness (RBE) is a central quantity in particle radiobiology and depends on many physical and biological factors. The local effect model (LEM) allows one to predict the RBE for radiobiologic experiments and particle therapy. In this work the sensitivity of the RBE on its determining factors is elucidated based on monitoring the RBE dependence on the input parameters of the LEM. The relevance and meaning of all parameters are discussed within the formalism of the LEM. While most of the parameters are fixed by experimental constraints, one parameter, the threshold dose Dt, may remain free and is then regarded as a fit parameter to the high LET dose response curve. The influence of each parameter on the RBE is understood in terms of theoretic considerations. The sensitivity analysis has been systematically carried out for fictitious in vitro cell lines or tissues with α/ß = 2 Gy and 10 Gy, either irradiated under track segment conditions with a monoenergetic beam or within a spread out Bragg peak. For both irradiation conditions, a change of each of the parameters typically causes an approximately equal or smaller relative change of the predicted RBE values. These results may be used for the assessment of treatment plans and for general uncertainty estimations of the RBE.

[Cardiac surgery in severe haemorrhagical diseases]. / Kardiochirurgische Eingriffe bei schweren Blutungsdiathesen.

Cardiovascular diseases are the most common disorder in the developed countries. Invasive cardiological and cardiosurgical techniques are known therapies. Yet, patients with severe hereditary haemorrhagical diseases (haemophilia, rare deficiencies of coagulation factors) have an increased bleeding risk by the use of anticoagulants. Therefore, the treatment of these patients requires a concomitant therapy. This article shows eight patients with a severe bleeding diathesis and cardiosurgical interventions in the years 2006 to 2011. This case report shall demonstrate that an adequate therapy can be accomplished with the help of a good cooperation between haemostaseologists and colleagues of the cardioinvasive/cardiosurgical disciplines.

[BEO'S - physical activity and healthy eating at schools in Oberfranken, Bavaria concept and first results of a resource-oriented, systemic approach in school-based health promotion]. / BEO'S - Bewegung und Ernährung an Oberfrankens Schulen Konzept und Erfahrungen bei der Umsetzung eines ressourcenorientierten, systemischen Ansatzes zur schulischen Gesundheitsförderung.

BACKGROUND: The high prevalence of overweight among children and adolescents has led to an increase in school-based prevention programmes. The aim of the present paper is to present the concept of an initiative called "BEO'S" as well as the experience made with the implementation und acceptance of this programme in the participating schools. METHODS: Different from the majority of school-based projects for healthy eating and physical activity, BEO'S pursues a systemic approach that includes the whole school and is tailored to the school's respective resources. Characteristics are (1) the participation of teachers, students, parents, and caretakers, (2) the motivation and empowerment of schools to plan and implement activities by themselves, (3) the focus on environmental approaches, and (4) addressing and considering the individual school's needs and resources. The university project team supports the schools by individual counselling as well as providing information materials, trainings and workshops for teachers, an internet page, newsletters, and financial support. In the school years 2007/08 and 2008/09, BEO'S was conducted at 14 primary and secondary schools in the district of Oberfranken, Bavaria. It was extended to other schools in 2009/10. The short- and mid-term goals are the improvement of the school's environments as well as the eating behaviour and physical activity of the students. In the long run, it is intended to prevent obesity and improve the students' health and school performance. RESULTS: The implementation processes showed that the teachers for physical education and domestic science as well as the headmasters were especially committed. The participation of the teaching staff, the students and the parents proved to be difficult, however. The schools implemented many activities for healthy eating and physical activity, but the planning process was not very systematic: needs assessment, status quo analysis, identification of successful strategies and definition of aims was difficult for the schools. The provided financial support, training programmes and workshops, and the exchange with other schools were widely used, in contrast to the offered internet-based tools. The acceptance of BEO'S was (very) good by teachers (n=97), students (n=674) and their parents (n=522). The teachers preferred the workshops and trainings to the internet page. The students appreciated the possibilities for physical activity and the emphasis on healthy eating; primary school students and girls more than secondary school students and boys. One third of the parents would like to be involved to a higher degree. CONCLUSION: BEO'S was well received by all the people involved. Yet, there are still deficits concerning the implementation process, especially in the participation of students and parents.

Listening to music and physiological and psychological functioning: the mediating role of emotion regulation and stress reactivity.

Music listening has been suggested to have short-term beneficial effects. The aim of this study was to investigate the association and potential mediating mechanisms between various aspects of habitual music-listening behaviour and physiological and psychological functioning. An internet-based survey was conducted in university students, measuring habitual music-listening behaviour, emotion regulation, stress reactivity, as well as physiological and psychological functioning. A total of 1230 individuals (mean = 24.89 ± 5.34 years, 55.3% women) completed the questionnaire. Quantitative aspects of habitual music-listening behaviour, i.e. average duration of music listening and subjective relevance of music, were not associated with physiological and psychological functioning. In contrast, qualitative aspects, i.e. reasons for listening (especially 'reducing loneliness and aggression', and 'arousing or intensifying specific emotions') were significantly related to physiological and psychological functioning (all p = 0.001). These direct effects were mediated by distress-augmenting emotion regulation and individual stress reactivity. The habitual music-listening behaviour appears to be a multifaceted behaviour that is further influenced by dispositions that are usually not related to music listening. Consequently, habitual music-listening behaviour is not obviously linked to physiological and psychological functioning.

Self-regulation following prostatectomy: phase-specific self-efficacy beliefs for pelvic-floor exercise.

OBJECTIVE: Beliefs in one's ability to perform a task or behaviour successfully are described as self-efficacy beliefs (Bandura, 1977). Since individuals have to deal with differing demands during a behaviour-change process, they form phase-specific self-efficacy beliefs directed at these respective challenges. The present study, based on the Health Action Process Approach (Schwarzer, 2001), examines the theoretical differentiation, relative importance, and differential effects of four phase-specific self-efficacy beliefs, including task self-efficacy, preactional self-efficacy, maintenance self-efficacy, and recovery self-efficacy. DESIGN: In a prospective longitudinal study, 112 prostatectomy-patients received questionnaires at 2 days, 2 weeks, 1 month, and 6 months post-surgery. METHODS: Participants provided data on phase-specific self-efficacies as well as phase indicators of health-behaviour change, that is, intentions, planning, and pelvic-floor exercise. Hierarchical regression analyses were conducted to test the study hypotheses. RESULTS: Task self-efficacy was not uniquely associated with intentions. Preactional self-efficacy was related to action planning. Maintenance self-efficacy did not predict behaviour. Recovery self-efficacy was associated with re-uptake of pelvic-floor exercise after relapses only. CONCLUSION: Findings underline the importance of differentiating between task self-efficacy and preactional self-efficacy during early phases of behaviour change as well as of considering the occurrence of relapses as a moderator of potential effects of recovery self-efficacy on the maintenance of behaviour change. Advanced knowledge on distinct, phase-specific self-efficacy beliefs may facilitate the design of effective tailored interventions for behaviour change.

[Von Willebrand disease type 1 and pregnancy]. / Von-Willebrand-Syndrom Typ 1 und Schwangerschaft.

The von Willebrand-Jürgens syndrome (VWJS) type 1 is a common hereditary bleeding disorder with a bleeding tendency located especially in the mucous membranes. Women suffering from VWJS type 1 show menorrhagia and prolonged postoperative bleedings. During pregnancy the clinical presentation varies by the increase of the von Willebrand factors. In this article the laboratory findings and the clinical presentation of patients with VWJS during pregnancy was examined. The necessity of interventions during pregnancy and at the time of delivery was under consideration.

[Caregiver burden with dementia patients. A validation study of the German language version of the Zarit Burden Interview]. / Die subjektive Belastung pflegender Ehepartner von Demenzkranken. Hinweise zur Validität der deutschen Version des Zarit Burden Interviews.

Despite the large number of studies dealing with dementia caregivers in Europe, a valid German version of the most widely used measurement of caregiver burden, the Zarit Burden Interview, has not been published. The purpose of this study was to evaluate the psychometric properties of the German Zarit Burden Interview (G-ZBI). A sample of community-dwelling older couples (n=37) with the husband suffering from dementia and the wife being the primary caregiver participated in this study. The G-ZBI and related constructs were assessed in order to test for reliability and construct validity. The G-ZBI revealed psychometric properties comparable with those of the original instrument and empirically validated translations. Results indicate high internal consistency (Cronbach's alpha=0.91) and good validity due to strong correlations with caregiver life satisfaction and depression, as well as patients' dependency, neuropsychiatric symptoms, and dementia severity. The psychometric qualities of the G-ZBI indicate that it is both a reliable and valid instrument to assess caregiver burden and to detect highly stressed individuals.

Disentangling the relation between intentions, planning, and behaviour: a moderated mediation analysis.

Action planning is assumed to mediate between intentions and health behaviours. Moreover, intentions are assumed to moderate the planning-behaviour relation, because people with high intentions are more likely to enact their plans. The present studies extend these suppositions by integrating both assumptions to a novel and parsimonious model of moderated mediation: the mediation effect is hypothesised to be stronger in individuals who report higher intention levels. In two longitudinal studies on physical activity (N = 124) and interdental hygiene (N = 209), intentions and action planning were assessed at baseline, and behaviour was measured four (Study 1), and respectively, three (Study 2) months later. The moderated mediation hypothesis was tested with continuously measured intentions using regression analyses with non-parametric bootstrapping. Results from both studies suggest that levels of intentions moderate the mediation process: The strength of the mediated effect increased along with levels of intentions. Planning mediates the intention-behaviour relation, if individuals hold sufficient levels of intentions. Implications for theory advancement and intervention development are discussed.

[The total ankle replacement for severe arthropathy in haemophilia]. / Die endoprothetische Versorgung des oberen Sprunggelenkes bei hämophiler Arthropathie.

The endoprosthetic surgery of the upper ankle joint in profound arthrosis has significantly increased over the last years. Along with the established arthodesis the alloarthroplastic became a good alternative. The main indication for the implantation of an ankle joint endoprosthesis is a secondary arthrosis in patients with rheumatic diseases or post-traumatic status. In accordance with our experience case reports on the total ankle arthroplasty in haemophilic arthropathy show that the artificial substitute of the upper ankle joint can be a successful treatment of these patients under certain conditions. The outstanding benefit is to be seen in the preservation of a sufficient mobility for everyday movements and a more physiological process of walking. In case of endoprosthetic failure a relatively save opportunity for revision in the mostly younger patients can be found in the new osteosynthesis techniques. Also in haemophilic arthropathy with painful advanced arthrosis and functional limitation of the upper ankle joint the endoprosthetic care can be taken into consideration.