Health-related quality of life, developmental milestones, and self-esteem in young adults with bleeding disorders.

BACKGROUND: The treatment of bleeding disorders improved in the last decades. However, the effect of growing up with bleeding disorders on developmental, emotional, and social aspects is understudied. Therefore, this study assesses HRQOL, developmental milestones, and self-esteem in Dutch young adults (YA) with bleeding disorders compared to peers. METHODS: Ninety-five YA (18-30 years) with bleeding disorders (78 men; mean 24.7 years, SD 3.5) and 17 women (mean 25.1 years, SD 3.8) participated and completed the Pediatric Quality of Life Inventory Young Adult version, the Course of Life Questionnaire, and the Rosenberg Self-Esteem Scale. Differences between patients with bleeding disorders and their peers, and between hemophilia severity groups, were tested using Mann-Whitney U tests. RESULTS: YA men with bleeding disorders report a slightly lower HRQOL on the total scale, physical functioning, and school/work functioning in comparison to healthy peers (small effect sizes). YA men with severe hemophilia report more problems on the physical functioning scale than non-severe hemophilia. YA men with bleeding disorders achieved more psychosexual developmental milestones than peers, but show a delay in 'paid jobs, during middle and/or high school.' A somewhat lower self-esteem was found in YA men with bleeding disorders in comparison to peers (small effect size). For YA women with bleeding disorders, no differences were found on any of the outcomes in comparison to peers. CONCLUSION: This study demonstrates some impairments in HRQOL and self-esteem in YA men with bleeding disorders. By monitoring HRQOL, problems can be identified early, especially with regard to their physical and professional/school functioning.

von Willebrand factor propeptide and the phenotypic classification of von Willebrand disease.

The ratios between von Willebrand factor propeptide (VWFpp) or factor VIII activity ( FVIII: C) and VWF antigen (VWF:Ag) reflect synthesis, secretion, and clearance of VWF. We aimed to define the pathophysiology of 658 patients with type 1, 2, or 3 von Willebrand disease (VWD) with VWF levels ≤30 U/dL from the Willebrand in The Netherlands (WiN) study using the VWFpp/VWF:Ag and FVIII: C/VWF:Ag ratios. We evaluated the use of VWFpp in the classification and diagnosis of VWD. On the basis of the ratios, reduced VWF synthesis was observed in 18% of type 1 and only 2% of type 2 patients. A significant proportion of type 3 patients had detectable VWFpp (41%). These patients had a lower bleeding score than type 3 patients who had a complete absence of VWF:Ag and VWFpp (14.0 vs 19.5; P = .025). The majority of these patients had missense mutations with rapid VWF clearance, whereas type 3 patients with no VWFpp were homozygous for null alleles. In conclusion, VWFpp identified severe type 1 VWD with very low VWF levels in patients who had previously been classified as type 3 VWD. This study underlines the clinical significance of the VWFpp assay in the diagnosis and classification of VWD.

Determination of the median effective dose (ED50 ) of spinal chloroprocaine in labour analgesia.

The primary goal of this study was to determine the median effective dose (ED50 ) of spinal chloroprocaine for labour analgesia. Thirty-eight parturients requesting neuraxial analgesia were enrolled. Doses of 1% chloroprocaine were determined by the technique of up-down sequential allocation, with an initial dose of 20 mg and steps of 2 mg. The chloroprocaine spinal dose was given as the spinal component of a combined spinal-epidural, which was then supplemented with an epidural dose of 7.5 µg sufentanil in 7 ml saline. Effective analgesia was defined as a score ≤ 10 mm within 15 min on a 100-mm visual analogue pain scale. Using the isotonic regression estimator method, the ED50 of chloroprocaine for the spinal component of a combined spinal-epidural for labour was calculated to be median (95%CI) 12.0 (9.3-17.0) mg.

Tachyphylaxis and reproducibility of desmopressin response in perioperative persons with nonsevere hemophilia A: implications for clinical practice.

Background: Desmopressin is frequently used perioperatively in persons with nonsevere hemophilia A. However, increase in factor (F)VIII:C after desmopressin use is interindividually highly variable. Tachyphylaxis has only been reported in test setting for persons with hemophilia A, with a remaining response of approximately 70% after a second dose compared with that after a first dose. Objectives: To study tachyphylaxis of FVIII:C response after multiple administration(s) of desmopressin in perioperative persons with nonsevere hemophilia A. Methods: We studied FVIII:C levels after desmopressin before (day 0 [D0]) and on days 1 (D1) and 2 (D2) after surgery in 26 patients of the DAVID and Little DAVID studies. We studied tachyphylaxis by comparing the responses at D1 and D2 with that at D0. We also assessed the reproducibility of the D0 response in comparison to an earlier performed desmopressin test. Results: The median absolute FVIII:C increase was 0.50 IU/mL (0.35-0.74; n = 23) at D0, 0.21 IU/mL (0.14-0.28; n = 17) at D1, and 0.23 IU/mL (0.16-0.30; n = 11) at D2. The median percentage of FVIII increase after the second administration (D1) compared with the first (D0) was 42.9% (29.2%-52.5%; n = 17) and that of the third (D2) compared with the first (D0) was 36.4% (23.7%-46.9%; n = 11). The FVIII:C desmopressin response at D0 was comparable with the desmopressin test response in 74% of the patients. Conclusion: Tachyphylaxis in the surgical setting was considerably more pronounced than previously reported, with FVIII:C at D1 and D2 of 36% to 43% of the initial response. Our results may have important implications for monitoring repeated desmopressin treatment when used perioperatively.

Basic principles for paediatric care: what ENT professionals should know.

Children undergoing medical or surgical treatment for ENT disorders should receive care from doctors familiar with the specificities of paediatric ENT pathology working in dedicated clinics where there are facilities for the activities that children usually indulge in and accommodation for parents. Many aspects of care for children with ENT problems involve a multidisciplinary team consisting of ENT surgeons working alongside a range of medical and paramedical professionals and nurses specifically trained in childcare, as well as in ENT nursing. Within this multidisciplinary approach, we will discuss some important aspects of the psychosocial approach and nursing, anaesthesia and pharmacotherapy that should be considered in order to raise the safety and quality of patient care in paediatric otorhinolaryngology.

Clinical implications and cost-effectiveness analysis of rivaroxaban in patients with coronary artery disease or peripheral arterial disease in the Netherlands.

BACKGROUND: Patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD) are at substantial risk of atherothrombotic events. The COMPASS trial showed that patients with stable CAD or PAD experienced significant benefits after treatment with rivaroxaban in combination with acetylsalicylic acid (ASA) compared with ASA alone. This paper aims to provide insight into the clinical and economic consequences of treatment with rivaroxaban from a Dutch societal perspective. METHODS: The clinical and economic implications of rivaroxaban in terms of the number of events prevented, costs, the incremental cost per life-years gained (LYG), and incremental cost per quality-adjusted life-years (QALYs) were determined based on a cost-effectiveness model for patients with stable CAD or PAD and in high-risk subgroups (i.e. patients with CAD and PAD, CAD and prior myocardial infarction and renal impairment, CAD and heart failure) using results from the Cardiovascular OutcoMes for People Using Anticoagulation Strategies (COMPASS) trial. RESULTS: Patients treated with rivaroxaban have an expected increased discounted life expectancy of 0.67 years. In high-risk groups discounted incremental life expectancy ranged from 1.33 to 1.90 years. The incremental cost-effectiveness ratio for the full COMPASS population was €9,760/LYG and €12,033/QALY, whereas, for high-risk subgroups of patients with underlying conditions, incremental cost-effectiveness ratios ranged from €2,966/LYG to €5,052/LYG and from €3,940/QALY to €6,815/QALY. Results from the sensitivity analyses revealed that the model results were robust to variations in single or multiple input parameters at once. CONCLUSIONS: The cost-effectiveness analysis showed that rivaroxaban in combination with ASA is a cost-effective treatment option in stable CAD or PAD patients. Rivaroxaban in combination with ASA is even more cost-effective in high-risk subgroups.

Study of the time course of the clinical effect of propofol compared with the time course of the predicted effect-site concentration: Performance of three pharmacokinetic-dynamic models.

BACKGROUND: In the ideal pharmacokinetic-dynamic (PK-PD) model for calculating the predicted effect-site concentration of propofol (Ce(PROP)), for any Ce(PROP), the corresponding hypnotic effect should be constant. We compared three PK-PD models (Marsh PK with Shüttler PD, Schnider PK with fixed ke0, and Schnider PK with Minto PD) in their ability to maintain a constant bispectral index (BIS), while using the respective effect-site-controlled target-controlled infusion (TCI) algorithms. METHODS: We randomized 60 patients to Group M (Marsh's model with k(e0)=0.26 min(-1)), Group S1 or Group S2 (Schnider's model with a fixed k(e0)=0.456 min(-1) or a k(e0) adapted to a fixed time-to-peak effect=1.6 min, respectively). All patients received propofol at a constant rate until loss of consciousness. The corresponding Ce(PROP), as calculated by the respective models, was set as a target for effect-site-controlled TCI. We observed BIS for 20 min. We hypothesized that BIS remains constant, if Ce(PROP) remains constant over time. RESULTS: All patients in Group M woke up, one in Group S1 and none in Group S2. In Groups S1 and S2, BIS remained constant after 11 min of constant Ce(PROP), at a more pronounced level of hypnotic drug effect than intended. CONCLUSIONS: Targeting Ce(PROP) at which patients lose consciousness with effect-site-controlled TCI does not translate into an immediate constant effect.

Kinetics and mechanism of the sphere-to-rod transition of triblock copolymer micelles in aqueous solutions.

The kinetics of the sphere-to-rod transition of micelles composed of triblock copolymers of ethylene oxide and propylene oxide (EO(20)PO(70)EO(20)) have been investigated using dynamic light scattering (DLS) and cryogenic electron transmission microscopy (Cryo-EM). Sphere-to-rod transition is induced by a solvent jump, initiated by adding KCl and ethanol to an aqueous micellar solution. The growth process of the wormlike micelles depends on the experimental conditions and has two distinct regions that can be described as initiation period and actual growth to equilibrium. All growth curves exhibit a single relaxation time that represents the lifetime of the micelles. The growth curves collapse into a master curve, when shifted by the relaxation time, indicating that the actual growth process of the micelles in all samples occurs through the same mechanism. The relaxation time decreases with increasing surfactant concentration. Additionally, some of the formed micelles exhibit a caterpillarlike shape in which some of the original spherical species can still be detected. These facts suggest that the micelles grow longer predominantly by random coagulation/fragmentation reactions involving micellar species of different sizes. However, the appearance of a unimer peak is detected with DLS during the growth stage. This implies that unimer exchange may also contribute to the elongation of the micelles.

Perioperative bridging of anticoagulation: towards a more reserved approach.

BACKGROUND: Most invasive procedures require the interruption of oral anticoagulation. In 2015, an international randomised trial demonstrated that perioperative bridging caused more harm than benefit in most anticoagulated patients with atrial fibrillation, leading to a more restrictive Dutch national guideline in April 2016. The objective of the present study was to analyse the integration of the 2016 Dutch guideline for perioperative antithrombotic management from after publication until update of hospital protocols. METHODS: This is a retrospective cohort study of patients on vitamin K antagonists undergoing a surgical procedure between April 2016 and June 2017. RESULTS: The proportion of high-risk patients with venous thromboembolism or atrial fibrillation receiving bridging therapy decreased from 91% and 77%, respectively at the start of the study to 33% in both groups in the last months. In high-risk patients with a mechanical heart valve, the bridging rate remained stable at 70-80% for 12 months and increased to 100% in the last 3 months. Protocol adherence for high-risk patients decreased from 80% to below 43%. The 30-day incidence of major bleeding was 4.1% (15.2% in bridged patients and 0.7% in non-bridged patients) and 10.3% for clinically relevant non-major bleeding (23.9% in bridged patients and 6.0% in non-bridged patients). The incidence of thrombo-embolism was 0.5%. CONCLUSION: New evidence from the Dutch national guideline on perioperative bridging was adopted by physicians before the local hospital protocol was updated. Low incidence of thromboembolism in non-bridged patients and high incidence of bleeding in bridged patients support a more restrictive bridging policy.

Effects of salts and ethanol on the population and morphology of triblock copolymer micelles in solution.

The morphological changes of micelles composed of triblock copolymer of ethylene oxide and propylene oxide (EO20PO70EO20) in the presence of different inorganic salts and ethanol have been investigated using dynamic light scattering (DLS), rheometry, and cryogenic transmission electron microscopy (cryo-EM). The following salts were studied: KF, KCl, KI, LiCl, and CsCl. In the presence of KF, KCl, and CsCl, spherical and wormlike micelles coexist. LiCl and KI have little influence on the morphology of the micelles, whereas KF has the most pronounced effect. In agreement with the well-known Hoffmeister anion salt series, F- has the strongest effect of the three anions studied (F-, Cl-, I-). In contrast, the effectiveness of the cation type does not follow the original Hoffmeister cation series. The addition of ethanol to the KCl micellar solutions leads to the formation of more or longer wormlike micelles, which start to interact at certain copolymer concentrations depending on the volume fraction of ethanol added. Both the dilute and the semidilute regimes of the wormlike micelles were studied. The length of the micelles reaches a maximum value at around 8-10 vol % ethanol, after which it decreases again. At higher ethanol concentrations (18 vol %), spherical micelles are formed. Conclusions from this study enhance our understanding of the role played by ethanol and salts in the formation of micelle-templated mesoporous materials, such as SBA-15.

Optimization of mesoporous titanosilicate catalysts for cyclohexene epoxidation via statistically guided synthesis.

An efficient approach to improve the catalytic activity of titanosilicates is introduced. The Doehlert matrix (DM) statistical model was utilized to probe the synthetic parameters of mesoporous titanosilicate microspheres (MTSM), in order to increase their catalytic activity with a minimal number of experiments. Synthesis optimization was carried out by varying two parameters simultaneously: homogenizing temperature and surfactant weight. Thirteen different MTSM samples were synthesized in two sequential 'matrices' according to Doehlert conditions and were used to catalyse the epoxidation of cyclohexene with tert-butyl hydroperoxide. The samples (and the corresponding synthesis conditions) with superior catalytic activity in terms of product yield and selectivity were identified. In addition, this approach revealed the limiting values of each synthesis parameter, beyond which the material becomes catalytically ineffective. This study demonstrates that the DM approach can be broadly used as a powerful and time-efficient tool for investigating the optimal synthesis conditions of heterogeneous catalysts.

Guidelines' risk assessment recommendations for venous thromboembolism prophylaxis: A comparison and implementability appraisal.

INTRODUCTION: Venous thromboembolism (VTE) prophylaxis guidelines for non-surgical patients recommend VTE- and bleeding risk assessment to guide prophylactic strategies. These recommendations differ between guidelines and implementation is suboptimal. Assessing a guideline's implementability characteristics helps predicting the ease of implementation and reveals barriers. OBJECTIVES: We aimed to compare guidelines' risk assessment recommendations and critically appraise the implementability characteristics. MATERIAL AND METHODS: Two guidelines, one from the American College of Chest Physicians and one from the National Institute for Health and Care Excellence were selected for comparison. Risk assessment methods and subsequent prophylactic recommendations were compared. Eight experts then appraised the guideline recommendations on intrinsic implementability characteristics using the GuideLine Implementability Appraisal (GLIA) instrument. GLIA identifies barriers and facilitators for guideline implementation in nine dimensions. RESULTS: Eleven out of 20 individual VTE-risk factors and 2 out of 19 individual bleeding-risk factors used, were present in both guidelines. Additionally, a high VTE- or bleeding risk was defined differently between the two guidelines. The GLIA appraisal identified implementation barriers within all recommendations analyzed. On content level, barriers were identified in recommendations addressing bleeding risk assessment, mechanical prophylaxis and critical care patients. On implementability level, barriers were identified in decidability, flexibility, effect on process of care and computability dimensions. CONCLUSION: Depending on the guideline used, VTE-prophylaxis will most likely be provided to different non-surgical patient populations, primarily due to discordance in bleeding risk assessment. Revising the recommendations, taking into account the most apparent implementation barriers, should be considered. However, insufficient evidence to support the recommendations currently complicates this.

Outcome of the subsequent pregnancy after a first loss in women with the factor V Leiden or prothrombin 20210A mutations.

BACKGROUND: The factor V Leiden (FVL) and prothrombin 20210A (PTm) mutations are associated with single late pregnancy loss and recurrent early pregnancy loss. The prognosis after an initial loss in women with thrombophilia is uncertain. OBJECTIVE: To assess the pregnancy outcome of the second pregnancy after a first loss in women with and without either FVL or PTm mutations. METHODS: We selected women with a first pregnancy loss out of two family cohorts of first degree relatives of probands with FVL or PTm mutations and a history of documented venous thromboembolism or premature atherosclerosis. RESULTS: Ninety-three women had had a first pregnancy loss and became pregnant a second time. Their risk of loss of the subsequent pregnancy was higher than in 825 women with a successful first pregnancy [25 vs. 12%, relative risk (RR) 2.0, 95% CI 1.4-3.0]. The live birth rate of the second pregnancy after an early first loss ( 12 weeks), the live birth rates were 68% (95% CI 46-85) and 80% (95% CI 49-94) for carriers and non-carriers, respectively (RR 0.9, 95% CI 0.5-1.3). CONCLUSIONS: Women with a first pregnancy loss have a 2-fold increased risk of loss of the subsequent pregnancy, regardless of their carrier status. More importantly, the outcome of the second pregnancy is rather favorable in absolute terms, even for those with thrombophilia and a late loss, which raises concern regarding the risks and presumed benefits of anticoagulant therapy in these women.