Search

To determine if a fixed dose of 1000 IU of 4-factor prothrombin complex concentrate (4F-PCC) is as effective as traditional variable dosing based on body weight and international normalized ratio (INR) for reversal of vitamin K antagonist (VKA) anticoagulation.

We conducted six cross‐sectional nationwide questionnaire studies among all patients with hemophilia in the Netherlands from 1972 until 2019 to assess how health outcomes have changed, with a special focus on patients >50 years of age. Data were collected on patient characteristics, treatment, (joint) bleeding, joint impairment, hospitalizations, human immunodeficiency virus and hepatitis C infections, and general health status (RAND‐36). In 2019, 1009 patients participated, of whom 48% had mild, 15% moderate, and 37% severe hemophilia. From 1972 to 2019, the use of prophylaxis among patients with severe hemophilia increased from 30% to 89%. Their median annual bleeding rate decreased from 25 to 2 bleeds. Patients with severe hemophilia aged <16 years reported joint impairment less often over time, but in those aged >40 years joint status did not improve. In 2019, 5% of all 1009 patients were positive for the human immunodeficiency virus. The proportion of patients with an active hepatitis C infection drastically decreased from 45% in 2001 to 2% in 2019 due to new anti‐hepatitis C treatment options. Twenty‐five percent had significant liver fibrosis even after successful therapy. Compared to the general male population, patients aged >50 years reported much lower scores on the RAND‐36, especially on physical functioning. Our study shows that increased use of prophylactic treatment and effective hepatitis C treatment have improved joint health and nearly eradicated hepatitis C infection in patients with hemophilia in the Netherlands. However, patients still suffer from hemophilia‐related complications, especially patients aged >50 years.

Treatment of patients with hemophilia has advanced over the past decades, but it is unknown whether this has resulted in a normal life expectancy in the Netherlands.

The emergence of highly active novel agents has led some to question the role of autologous haematopoietic stem-cell transplantation (HSCT) and subsequent consolidation therapy in newly diagnosed multiple myeloma. We therefore compared autologous HSCT with bortezomib–melphalan–prednisone (VMP) as intensification therapy, and bortezomib–lenalidomide–dexamethasone (VRD) consolidation therapy with no consolidation.

Type 2B von Willebrand disease (VWD) is a bleeding disorder caused by gain-of-function variants in the VWFgene. The laboratory and clinical phenotype of type 2B VWD is heterogeneous.

Marin is designing and building a modular autonomous underwater vehicle (mAUV). The vehicle will serve as a platform for research projects to be carried out in our model test basins. The modular design will enable future extensions with additional sensors and actuators. The design of the vehicle and its control system is aimed at combining capabilities for position keeping (zero speed) and track sailing (medium and high speed). The vehicle is controlled in all 6 degrees of freedom, without any a-priori limitations.

MARIN is designing and building a modular autonomous underwater vehicle (mAUV). The vehicle will serve as a platform for research projects on autonomous vehicles, to be carried out in our model basins. The modular design will enable future extensions with additional sensors and actuators. The design of the vehicle and its control system is aimed at combining capabilities for position keeping (zero speed) and track sailing (medium and high speed). The vehicle is controlled in all 6 degrees of freedom, without any a priori limitations. This paper discusses the design and construction of the vehicle. The overall design of the vehicle is discussed, as well as the selected actuators and all internal mechanical, electrical and instrumentation systems.

Background:Hemato-oncological patients, and in particular patients with acute myeloid leukemia (AML) in the remission induction treatment phase frequently receive transfusion products. These products include platelet- and red blood cell- concentrates and are administered in order to prevent and treat bleeding complications and anemia. During this treatment, patients are constantly monitored by clinical laboratory tests, however, additional studies could add nuanced information about the patients' status. Different studies have shown that plasma proteins change and their patterns' characteristics could be key to illustrate the patients' healthy and/or disease status. Importantly, changes in the plasma proteome in AML patients receiving transfusion products have not yet been studied. Thus, defining protein profiles during this phase is vital to use as a point of reference prior to tracing patients' treatments and their responses.

Introduction:Rilzabrutinib is a potent oral, reversible Bruton tyrosine kinase inhibitor that can treat hematological autoimmune diseases through multiple putative mechanisms of action: (1) inhibition of B-cell activation, (2) interruption of antibody-coated cell phagocytosis by FcϒR in spleen and liver, and (3) induce sustained anti-inflammatory effects (Langrish J Immunol2021). Preliminary evidence showed that rilzabrutinib treatment resulted in rapid and durable platelet responses with a favorable safety profile in previously treated patients with immune thrombocytopenia (ITP) as studied in part A of a phase 1/2 clinical study (LUNA 2; Kuter N Engl J Med2022). This abstract summarizes the results of part B that focused on the durability of response with rilzabrutinib in relapsed ITP patients.

Introduction

Pathogen inactivation of platelet concentrates reduces the risk for blood-borne infections. However, its effect on platelet function and hemostatic efficacy of transfusion is unclear. We conducted a randomized noninferiority trial comparing the efficacy of pathogen-inactivated platelets using riboflavin and UV B illumination technology (intervention) compared with standard plasma-stored platelets (control) for the prevention of bleeding in patients with hematologic malignancies and thrombocytopenia. The primary outcome parameter was the proportion of transfusion-treatment periods in which the patient had grade 2 or higher bleeding, as defined by World Health Organization criteria. Between November 2010 and April 2016, 469 unique patients were randomized to 567 transfusion-treatment periods (283 in the control arm, 284 in the intervention arm). There was a 3% absolute difference in grade 2 or higher bleeding in the intention-to-treat analysis: 51% of the transfusion-treatment periods in the control arm and 54% in the intervention arm (95% confidence interval [CI], −6 to 11; P = .012 for noninferiority). However, in the per-protocol analysis, the difference in grade 2 or higher bleeding was 8%: 44% in the control arm and 52% in the intervention arm (95% CI −2 to 18; P = .19 for noninferiority). Transfusion increment parameters were ∼50% lower in the intervention arm. There was no difference in the proportion of patients developing HLA class I alloantibodies. In conclusion, the noninferiority criterion for pathogen-inactivated platelets was met in the intention-to-treat analysis. This finding was not demonstrated in the per-protocol analysis. This trial was registered at The Netherlands National Trial Registry as #NTR2106 and at www.clinicaltrials.gov as #NCT02783313.

Recipients of autologous haemopoietic stem-cell transplants (auto-HSCT) have an increased risk of herpes zoster and herpes zoster-related complications. The aim of this study was to establish the efficacy and safety of an inactivated varicella zoster vaccine for the prevention of herpes zoster after auto-HSCT.

The Dutch-Belgian Cooperative Trial Group for Hematology Oncology Group-65/German-speaking Myeloma Multicenter Group-HD4 (HOVON-65/GMMG-HD4) phase III trial compared bortezomib (BTZ) before and after high-dose melphalan and autologous stem cell transplantation (HDM, PAD arm) compared with classical cytotoxic agents prior and thalidomide after HDM (VAD arm) in multiple myeloma (MM) patients aged 18–65 years. Here, the long-term follow-up and data on second primary malignancies (SPM) are presented. After a median follow-up of 96 months, progression-free survival (censored at allogeneic transplantation, PFS) remained significantly prolonged in the PAD versus VAD arm (hazard ratio (HR)=0.76, 95% confidence interval (95% CI) of 0.65–0.89, P=0.001). Overall survival (OS) was similar in the PAD versus VAD arm (HR=0.89, 95% CI: 0.74–1.08, P=0.24). The incidence of SPM were similar between the two arms (7% each, P=0.73). The negative prognostic effects of the cytogenetic aberration deletion 17p13 (clone size ⩾10%) and renal impairment at baseline (serum creatinine >2 mg dl−1) on PFS and OS remained abrogated in the PAD but not VAD arm. OS from first relapse/progression was similar between the study arms (HR=1.02, P=0.85). In conclusion, the survival benefit with BTZ induction/maintenance compared with classical cytotoxic agents and thalidomide maintenance is maintained without an increased risk of SPM.

The prognosis of multiple myeloma (MM) patients who become refractory to lenalidomide and bortezomib is very poor, indicating the need for new therapeutic strategies for these patients. Next to the development of new drugs, the strategy of combining agents with synergistic activity may also result in clinical benefit for patients with advanced myeloma. We have previously shown in a retrospective analysis that lenalidomide combined with continuous low-dose cyclophosphamide and prednisone (REP) had remarkable activity in heavily pretreated, lenalidomide-refractory MM patients. To evaluate this combination prospectively, we initiated a phase 1/2 study to determine the optimal dose and to assess its efficacy and safety in lenalidomide-refractory MM patients. The maximum tolerated dose (MTD) was defined as 25 mg lenalidomide (days 1-21/28 days), combined with continuous cyclophosphamide (50 mg/d) and prednisone (20 mg/d). At the MTD (n = 67 patients), the overall response rate was 67%, and at least minimal response was achieved in 83% of the patients. Median progression-free survival and overall survival were 12.1 and 29.0 months, respectively. Similar results were achieved in the subset of patients with lenalidomide- and bortezomib-refractory disease as well as in patients with high-risk cytogenetic abnormalities, defined as t(4;14), t(14;16), del(17p), and/or ampl(1q) as assessed by fluorescence in situ hybridization. Neutropenia (22%) and thrombocytopenia (22%) were the most common grade 3-4 hematologic adverse events. Infections (21%) were the most common grade 3-5 nonhematologic adverse events. In conclusion, the addition of continuous low-dose oral cyclophosphamide to lenalidomide and prednisone offers a new therapeutic perspective for multidrug refractory MM patients. This trial was registered at www.clinicaltrials.gov as #NCT01352338.

Females and males differ significantly in the prevalence and presentation of autism spectrum conditions. One theory of this effect postulates that autistic traits lie on a sex-related continuum in the general population, and autism represents the extreme male end of this spectrum. This theory predicts that any feature of autism in males should 1) be present in autistic females, 2) differentiate between the sexes in the typical population, and 3) correlate with autistic traits. We tested these three predictions for default mode network (DMN) hypoconnectivity during the resting state, one of the most robustly found neurobiological differences in autism.

The East Australian Current (EAC) is the western boundary current flowing along the east coast of Australia separating from the coast at approximately 34°S. After the separation two main pathways can be distinguished, the eastward flowing Tasman Front and the extension of the EAC flowing southward. The area south of the separation latitude is eddy‐rich and the separation latitude of the EAC is variable. Little is known of the properties of the water masses that separate at the bifurcation of the EAC. This paper presents new insights from the Lagrangian perspective, where the water masses that veer east and those that continue south are tracked in an eddy‐permitting numerical model. The transport along the two pathways is computed, and a 1:3 ratio between transport in the EAC extension and transport in the Tasman Front is found. The results show that the “fate” of the particles is to first order already determined by the particle distribution within the EAC current upstream of the separation latitude, where 85% of the particles following the EAC extension originate from below 460 m and 90% of the particles following the Tasman Front originate from the top 460 m depth at 28°S. The separation and pathways are controlled by the structure of the isopycnals in this region. Analysis of anomalies in potential vorticity show that in the region where the two water masses overlap, the fate of the water depends on the presence of anticyclonic eddies that push isopycnals down and therefore enable particles to travel further south. The East Australia Current separates at 34°SControls on fate of water are investigatedDepth of water is main control, with deep water flowing south

von Willebrand factor (VWF) levels in healthy individuals are influenced by variations in genetic loci other than the VWFgene, whose contribution to VWF levels in patients with von Willebrand disease (VWD) is largely unknown.

Because the number of elderly von Willebrand disease (VWD) patients is increasing, the pathophysiology of aging in VWD has become increasingly relevant.