Patient with knee osteoarthritis demonstrates improved knee adduction moment after knee joint distraction: a case report.

In this article we report a case of a 53-year-old patient diagnosed with end-stage osteoarthritis (OA) of the knee. The patient underwent treatment with knee joint distraction (KJD) with the aim to postpone total knee arthroplasty and prevent potential revision surgery. To assess the effect of KJD, a 3D gait analysis was performed preoperative and one year postoperative. In this patient, preoperative 3D gait analysis revealed an increased knee adduction moment (KAM) compared to healthy levels. Postoperative the KAM decreased, approaching healthy levels, suggesting potential improvements in disease status or in gait. Consequently, further investigation into the effectiveness of Knee Joint Distraction (KJD) as a treatment option for relatively young patients with knee OA is warranted. Gait analysis has emerged as an effective tool for assessing treatment outcomes of innovative treatment such as KJD at the individual level.

Physical Functioning in Patients with a Recent Fracture: The "Can Do, Do Do" Framework Applied to Explore Physical Capacity, Physical Activity and Fall Risk Factors.

Physical capacity (PC) and physical activity (PA) are associated physical performance measures, and combined, PC and PA are used to categorize physical performance in the "can do, do do" framework. We aimed to explore physical performance of patients attending the fracture liaison service (FLS). In this cross-sectional study, PC was measured by 6-min-walking-test (can't do/can do) and PA by accelerometer (don't do/do do). Following quadrants were defined based on predefined cut-off scores for poor performance: (1) "can't do, don't do"; (2) "can do, don't do"; (3) "can't do, do do"; (4) "can do, do do". Odds ratios (OR) were calculated and fall and fracture risk factors were assessed between quadrants. Physical performance of 400 fracture patients was assessed (mean age 64; female 70.8%). Patients performed as follows: 8.3% "can't do, don't do"; 3.0% "can do, don't do"; 19.3% "can't do, do do"; 69.5% "can do, do do". For the "can't do" group the OR for low PA was 9.76 (95% CI: 4.82-19.80). Both the "can't do, don't do" and "can't do, do do" group differed significantly compared to the "can do, do do" group on several fall and fracture risk factors and had lower physical performance. The "can do, do do" framework is able to identify fracture patients with an impaired physical performance. Of all FLS patients 20% "can't do, but "do do" while having a high prevalence of fall risk factors compared to persons that "can do, do do", which may indicate this group is prone to fall.

Therapeutically dosed low molecular weight heparins in renal impairment: a nationwide survey.

PURPOSE: International guidelines vary in their recommendations whether or not to reduce the therapeutic dose of low molecular weight heparins (LMWHs) in renal impairment. The use of anti-Xa monitoring as a basis of dose adjustments is also a matter of debate. As this may lead to variations in treatment policies, we aimed to study the treatment policies of therapeutically dosed LMWHs in renal impairment in Dutch hospitals. METHODS: An 11-item survey was distributed between June 2020 and March 2021 to hospital pharmacists, representing Dutch hospital organisations. Primary outcomes were the dosing regimens of therapeutically dosed LMWHs in renally impaired patients. Secondary outcomes were the proportion of hospitals that used anti-Xa monitoring and the anti-Xa target range used. RESULTS: There was a response from 56 of 69 (81%) Dutch hospital organisations where in each case a hospital pharmacist completed the survey. In these hospitals, 77 LMWH regimens were in use. In 76 of 77 (99%) regimens, a regular dose reduction was used at the start of treatment. Fifty-five of these hospitals used a dose reduction if estimated glomerular filtration rate (eGFR) < 50 ml/min and 17 used a dose reduction if eGFR < 30 ml/min. Anti-Xa levels were not routinely monitored in 40% of regimens, while 22% monitored anti-Xa if eGFR < 50 ml/min, 27% if eGFR < 30 ml/min and 10% in other eGFR cutoff values. Target ranges of 1.0-2.0 IU/ml (once daily) and 0.5/0.6-1.0 IU/ml (twice daily) were used in 69% of regimens that included monitoring of anti-Xa. CONCLUSION: Treatment policies show substantial diversity in therapeutically dosed LMWHs in renally impaired patients. The most commonly used treatment regimen was a regular dose reduction if eGFR is < 50 ml/min, without anti-Xa monitoring.

In silico evaluation of limited sampling strategies for individualized dosing of extended half-life factor IX concentrates in hemophilia B patients.

PURPOSE: Hemophilia B is a bleeding disorder, caused by a factor IX (FIX) deficiency. Recently, FIX concentrates with extended half-life (EHL) have become available. Prophylactic dosing of EHL-FIX concentrates can be optimized by assessment of individual pharmacokinetic (PK) parameters. To determine these parameters, limited sampling strategies (LSSs) may be applied. The study aims to establish adequate LSSs for estimating individual PK parameters of EHL-FIX concentrates using in silico evaluation. METHODS: Monte Carlo simulations were performed to obtain FIX activity versus time profiles using published population PK models for N9-GP (Refixia), rFIXFc (Alprolix), and rIX-FP (Idelvion). Fourteen LSSs, containing three or four samples taken within 8 days after administration, were formulated. Bayesian analysis was applied to obtain estimates for clearance (CL), half-life (t1/2), time to 1% (Time1%), and calculated weekly dose (Dose1%). Bias and precision of these estimates were assessed to determine which LSS was adequate. RESULTS: For all PK parameters of N9-GP, rFIXFc and rIX-FP bias was generally acceptable (range: -5% to 5%). For N9-GP, precision of all parameters for all LSSs was acceptable (< 25%). For rFIXFc, precision was acceptable for CL and Time1%, except for t1/2 (range: 27.1% to 44.7%) and Dose1% (range: 12% to 29.4%). For rIX-FP, all LSSs showed acceptable bias and precision, except for Dose1% using LSS with the last sample taken on day 3 (LSS 6 and 10). CONCLUSION: Best performing LSSs were LSS with samples taken at days 1, 5, 7, and 8 (N9-GP and rFIXFc) and at days 1, 4, 6, and 8 (rIX-FP), respectively.

Real-world keystroke dynamics are a potentially valid biomarker for clinical disability in multiple sclerosis.

BACKGROUND: Clinical measures in multiple sclerosis (MS) face limitations that may be overcome by utilising smartphone keyboard interactions acquired continuously and remotely during regular typing. OBJECTIVE: The aim of this study was to determine the reliability and validity of keystroke dynamics to assess clinical aspects of MS. METHODS: In total, 102 MS patients and 24 controls were included in this observational study. Keyboard interactions were obtained with the Neurokeys keyboard app. Eight timing-related keystroke features were assessed for reliability with intraclass correlation coefficients (ICCs); construct validity by analysing group differences (in fatigue, gadolinium-enhancing lesions on magnetic resonance imaging (MRI), and patients vs controls); and concurrent validity by correlating with disability measures. RESULTS: Reliability was moderate in two (ICC = 0.601 and 0.742) and good to excellent in the remaining six features (ICC = 0.760-0.965). Patients had significantly higher keystroke latencies than controls. Latency between key presses correlated the highest with Expanded Disability Status Scale (r = 0.407) and latency between key releases with Nine-Hole Peg Test and Symbol Digit Modalities Test (ρ = 0.503 and r = -0.553, respectively), ps < 0.001. CONCLUSION: Keystroke dynamics were reliable, distinguished patients and controls, and were associated with clinical disability measures. Consequently, keystroke dynamics are a promising valid surrogate marker for clinical disability in MS.

Longitudinal associations of light-intensity physical activity with quality of life, functioning and fatigue after colorectal cancer.

PURPOSE: Evidence from cross-sectional studies suggests that higher levels of light-intensity physical activity (LPA) are associated with better health-related quality of life (HRQoL) in colorectal cancer (CRC) survivors. However, these associations have not been investigated in longitudinal studies that provide the opportunity to analyse how within-individual changes in LPA affect HRQoL. We investigated longitudinal associations of LPA with HRQoL outcomes in CRC survivors, from 6 weeks to 2 years post-treatment. METHODS: Data were used of a prospective cohort study among 325 stage I-III CRC survivors (67% men, mean age: 67 years), recruited between 2012 and 2016. Validated questionnaires were used to assess hours/week of LPA (SQUASH) and HRQoL outcomes (EORTC QLQ-C30, Checklist Individual Strength) at 6 weeks, and 6, 12 and 24 months post-treatment. We applied linear mixed regression to analyse longitudinal confounder-adjusted associations of LPA with HRQoL. RESULTS: We observed statistically significant longitudinal associations between more LPA and better global quality of life and physical, role and social functioning, and less fatigue over time. Intra-individual analysis showed that within-person increases in LPA (per 8 h/week) were related to improved HRQoL, including better global quality of life (ß = 1.67, 95% CI 0.71; 2.63; total range scale: 0-100) and less fatigue (ß = - 1.22, 95% CI - 2.37; - 0.07; scale: 20-140). Stratified analyses indicated stronger associations among participants below the median of moderate-to-vigorous physical activity (MVPA) at diagnosis. CONCLUSION: Higher levels of LPA were longitudinally associated with better HRQoL and less fatigue in CRC survivors up to two years post-treatment. Further prospective studies using accelerometer data are necessary to inform development of interventions targeting LPA.

Gait in patients with symptomatic osteoporotic vertebral compression fractures over 6 months of recovery.

BACKGROUND: One factor related to disability in people with spinal deformity is decreased postural control and increased risk of falling. However, little is known about the effect of osteoporotic vertebral compression fractures (OVCFs) and their recovery on gait and stability. Walking characteristics of older adults with and without vertebral fractures have not yet been compared. AIMS: The purpose of the current study was to examine the spatiotemporal gait parameters and their variability in patients with an OVCF and healthy participants during treadmill walking at baseline and after 6 months of recovery. METHODS: Twelve female patients suffering a symptomatic OVCF were compared to 11 matched controls. Gait analysis was performed with a dual-belt instrumented treadmill with a 180° projection screen providing a virtual environment (computer-assisted rehabilitation environment). Results of patients with an OVCF and healthy participants were compared. Furthermore, spatiotemporal gait parameters were assessed over 6 months following the fracture. RESULTS: Patients suffering from an OVCF appeared to walk with significantly shorter, faster and wider strides compared to their healthy counterparts. Although stride time and length improved over time, the majority of the parameters analysed remained unchanged after 6 months of conservative treatment. DISCUSSION: Since patients do not fully recover to their previous level of mobility after 6 months of conservative treatment for OVCF, it appears of high clinical importance to add balance and gait training to the treatment algorithm of OVCFs. CONCLUSIONS: Patients suffering from an OVCF walk with shorter, faster and wider strides compared to their healthy counterparts adopt a less stable body configuration in the anterior direction, potentially increasing their risk of forward falls if perturbed. Although stride time and stride length improve over time even reaching healthy levels again, patients significantly deviate from normal gait patterns (e.g. in stability and step width) after 6 months of conservative treatment.

Women prefer proactive support from providers for treatment of heavy menstrual bleeding: A qualitative study in adult women with moderate or severe Von Willebrand disease.

OBJECTIVE: To explore key factors for successful support in women with moderate or severe Von Willebrand disease (VWD) who are faced with heavy menstrual bleeding (HMB) and surgery. DESIGN: A qualitative study design with focus-group interviews and thematic analysis of the discussions. SETTINGS AND POPULATION: Eleven VWD women aged 41-68 years (median age 58 years) who had had a hysterectomy or bipolar radiofrequency ablation (BRA) because of HMB participated in this study. Three of the 11 participants had VWD diagnosed before surgery. Two focus groups were conducted in the summer of 2012. Patients were identified through participation in a nationwide study on Von Willebrand disease in the Netherlands (WiN study). Inclusion criteria were at least 18 years of age, fluent in Dutch, diagnosed with VWD (based on Von Willebrand factor (VWF) antigen and/or activity levels < 30 IU/dL) and previous surgical therapy for HMB. FINDINGS: The following key factors were identified during focus-group interviews: receiving information, proactive support from providers and considering bleeding disorders as a cause of HMB. Other topics were as follows: experiences with VWD and/or surgery, how relieved patients were when menses stopped, patients hoped that in future, providers would work better together so that women receive the best care. CONCLUSIONS: In this focus-group study among women with VWD who underwent surgery because of HMB, support by professionals could be improved by considering a bleeding disorder in women with HMB, providing information about different types of surgery and shared decision-making regarding type of interventions.

Analysis of current perioperative management with Haemate® P/Humate P® in von Willebrand disease: Identifying the need for personalized treatment.

INTRODUCTION: Patients with Von Willebrand disease (VWD) are regularly treated with VWF-containing concentrates in case of acute bleeding, trauma and dental or surgical procedures. AIM: In this multicentre retrospective study, current perioperative management with a von Willebrand factor (VWF)/Factor VIII (FVIII) concentrate (Haemate® P) in patients with VWD was evaluated. PATIENTS/METHODS: Patients with VWD undergoing minor or major surgery between 2000 and 2015, requiring treatment with a VWF/FVIII concentrate (Haemate® P), were included. Achieved VWF activity (VWF:Act) and FVIII during FVIII-based treatment regimens were compared to predefined target levels in national guidelines. RESULTS: In total, 103 patients with VWD (148 surgeries) were included: 54 type 1 (73 surgeries), 43 type 2 (67 surgeries) and 6 type 3 (8 surgeries). Overall, treatment resulted in high VWF:Act and FVIII levels, defined as ≥0.20 IU/mL above predefined levels. In patients with type 1 VWD, respectively, 65% and 91% of trough VWF:Act and FVIII levels were higher than target levels. In patients with type 2 and type 3 VWD, respectively, 53% and 57% of trough VWF:Act and 72% and 73% of trough FVIII levels were higher than target level. Furthermore, FVIII accumulation over time was observed, while VWF:Act showed a declining trend, leading to significantly higher levels of FVIII than VWF:Act. CONCLUSION: High VWF:Act and accumulation of FVIII were observed after perioperative FVIII-based replacement therapy in patients with VWD, both underlining the necessity of personalization of dosing regimens to optimize perioperative treatment.

Perioperative replacement therapy in haemophilia B: An appeal to "B" more precise.

INTRODUCTION: Haemophilia B is caused by a deficiency of coagulation factor IX (FIX) and characterized by bleeding in muscles and joints. In the perioperative setting, patients are treated with FIX replacement therapy to secure haemostasis. Targeting of specified FIX levels is challenging and requires frequent monitoring and adjustment of therapy. AIM: To evaluate perioperative management in haemophilia B, including monitoring of FIX infusions and observed FIX levels, whereby predictors of low and high FIX levels were assessed. METHODS: In this international multicentre study, haemophilia B patients with FIX < 0.05 IU mL-1 undergoing elective, minor or major surgical procedures between 2000 and 2015 were included. Data were collected on patient, surgical and treatment characteristics. Observed FIX levels were compared to target levels as recommended by guidelines. RESULTS: A total of 255 surgical procedures were performed in 118 patients (median age 40 years, median body weight 79 kg). Sixty percent of FIX levels within 24 hours of surgery were below target with a median difference of 0.22 IU mL-1 [IQR 0.12-0.36]; while >6 days after surgery, 59% of FIX levels were above target with a median difference of 0.19 IU mL-1 [IQR 0.10-0.39]. Clinically relevant bleeding complications (necessity of a second surgical intervention or red blood cell transfusion) occurred in 7 procedures (2.7%). CONCLUSION: This study demonstrates that targeting of FIX levels in the perioperative setting is complex and suboptimal, but although this bleeding is minimal. Alternative dosing strategies taking patient and surgical characteristics as well as pharmacokinetic principles into account may help to optimize and individualize treatment.

Strength exercises during physical education classes in secondary schools improve body composition: a cluster randomized controlled trial.

BACKGROUND: Metabolic health in people with obesity is determined by body composition. In this study, we examined the influence of a combined strength exercise and motivational programme -embedded in the school curriculum- on adolescents body composition and daily physical activity. METHODS: A total of 695 adolescents (11-15y) from nine Dutch secondary schools participated in a one year cluster randomised controlled trial (RCT). In the intervention schools, physical education teachers were instructed to spend 15-30 min of all physical education lessons (2× per week) on strength exercises. Monthly motivational lessons were given to stimulate students to be more physically active. Control schools followed their usual curriculum. The primary outcome measure was body composition assessed by the deuterium dilution technique. Daily physical activity and sedentary behaviour measured by accelerometry served as a secondary outcome. RESULTS: After 1 year, a 1.6% fat mass difference was found in favour of the intervention group (p = .007). This reflected a 0.9 kg difference in fat free mass (intervention>control; p = .041) and 0.7 kg difference in fat mass (intervention

Wild mice in and around the city of Utrecht, the Netherlands, are carriers of Clostridium difficile but not ESBL-producing Enterobacteriaceae, Salmonella spp. or MRSA.

Mice in buildings are a hygiene hazard because they harbour several zoonoses and animal diseases. The aim of this study was to gather information on specific bacteria in house mice caught in the urban environment. Mice caught in snap traps during pest control activities were collected in and around the city of Utrecht, the Netherlands, during May-June 2014, October-November 2015 and September-November 2016. The gut contents were analysed for ESBL/AmpC-producing Enterobacteriaceae, Salmonella spp., and Clostridium difficile and the buccal cavities were swabbed for methicillin-resistant S. aureus (MRSA). In total, 109 house mice (Mus musculus) and 22 wood mice (Apodemus sylvaticus) were examined. One mouse was found positive for Enterobacter spp. Salmonella spp. and MRSA were not found. Of n = 80 mice, 35·0% carried C. difficile (ribotypes in descending order of frequency: 014/020, 258, 002, 005, 013, 056, 081 and two unknown ribotypes). In conclusion, mouse droppings are a hazard for transmission of C. difficile to humans and their environment. SIGNIFICANCE AND IMPACT OF THE STUDY: This study shows that mice in buildings can carry Clostridium difficile ribotypes that are associated with clinical disease in humans. Whether the mice are the source or whether they picked up these bacteria from the human environment has not been investigated. Either way, mouse droppings in the indoor environment are a hazard for transmission of C. difficile to humans.

Gait analysis and functional outcome in patients after Lisfranc injury treatment.

INTRODUCTION: Lisfranc injuries involve any bony or ligamentous disruption of the tarsometatarsal joint. Outcome results after treatment are mainly evaluated using patient-reported outcome measures (PROM), physical examination and radiographic findings. Less is known about the kinematics during gait. METHODS: Nineteen patients (19 feet) treated for Lisfranc injury were recruited. Patients with conservative treatment and surgical treatment consisting of open reduction and internal fixation (ORIF) or primary arthrodesis were included. PROM, radiographic findings and gait analysis using the Oxford Foot Model (OFM) were analysed. Results were compared with twenty-one healthy subjects (31 feet). Multivariable logistic regression was used to determine factors influencing outcome. RESULTS: Patients treated for Lisfranc injury had a significantly lower walking speed than healthy subjects (P<0.001). There was a significant difference between the two groups regarding the range of motion (ROM) in the sagittal plane (flexion-extension) in the midfoot during the push-off phase (p<0.001). The ROM in the sagittal plane was significantly correlated with the AOFAS midfoot score (r2=0.56, p=0.012), FADI (r2=0.47, p=0.043) and the SF-36-physical impairment score (r2=0.60, p=0.007) but not with radiographic parameters for quality of reduction. In a multivariable analysis, the best explanatory factors were ROM in the sagittal plane during the push-off phase (ß=0.707, p=0.001), stability (ß=0.423, p=0.028) and BMI (ß=-0.727 p=<0.001). This prediction model explained 87% of patient satisfaction. CONCLUSIONS: This study showed that patients treated for Lisfranc injury had significantly lower walking speed and significantly lower flexion/extension in the midfoot than healthy subjects. The ROM in these patients was significantly correlated with PROM, but not with radiographic quality of reduction. Most important satisfaction predictors were BMI, ROM in the sagittal plane during the push-off phase and fracture stability.

Driving restrictions for Dutch patients with an implantable cardioverter defibrillator : Compliance and associated factors.

BACKGROUND: Dutch patients with an implantable cardioverter defibrillator (ICD) are restricted from driving for two months after implantation or shocks. This requires significant lifestyle adjustments and is one of the primary concerns of ICD patients. Previous studies indicated that compliance with the driving restrictions is poor, but insight in socio-demographic, clinical and psychological factors associated with compliance is limited. Hence, this study aimed to explore compliance with the driving restrictions and associated factors in a large sample of Dutch ICD patients. METHOD: Dutch ICD patients (N = 313) completed an elaborative set of questionnaires at time of implantation and at four months after implantation, assessing socio-demographic, psychological and driving-related characteristics. Clinical data were collected from the patients' medical records. RESULTS: A substantial subgroup (28%) of the patient sample (median age 64 (interquartile range = 55-71), 81% male) reported to have been noncompliant with the driving restrictions. Univariate analysis indicated that noncompliant patients more often considered refusing the ICD due to the restrictions, compared to compliant patients (19% versus 10%, p = 0.02). Multivariate analysis showed that the feeling of understanding the reason behind the driving restrictions was associated with better compliance (odds ratio = 2.16, 95% confidence interval 1.02-4.56, p = 0.04). No other socio-demographic, clinical, psychological or driving-related factors were associated with compliance. CONCLUSION: A large number of ICD patients does not comply with the driving restrictions after implantation. This study emphasised the importance of the patient's feeling of understanding the reason behind the restrictions.

Plasma levels of plasminogen activator inhibitor-1 and bleeding phenotype in patients with von Willebrand disease.

INTRODUCTION: von Willebrand disease (VWD) is the most common inherited bleeding disorder. In VWD patients, large variations in bleeding tendency are observed, which cannot be completely explained by the variation in von Willebrand factor levels or activities. Thus, there must be additional factors, for instance, changes in fibrinolysis that have an effect on the variation in bleeding tendency in VWD patients. AIM: To investigate whether plasminogen activator inhibitor-1 (PAI-1) level influences the variation in bleeding tendency in VWD patients. METHODS: PAI-1 antigen levels were measured in the plasma of 633 patients with moderate or severe VWD who participated in the 'Willebrand in the Netherlands' (WiN) study, a nationwide multicentre cross-sectional study. Bleeding severity was assessed using the Tosetto bleeding score. RESULTS: PAI-1 levels increased with age (Spearman's rho: 0.225, P < 0.001) and were higher in men (23 [IQR 12-60] vs. 20 [IQR 10-44] ng mL-1 in women, P = 0.039), whereas the bleeding score was higher in women (11 [IQR 7-17] vs. 9 [IQR 5-14] ng mL-1 in men, P = 0.002). After adjustment for age and sex by stratification, PAI-1 level and bleeding score were negatively correlated (Spearman's rho: -0.170, P = 0.017) in the group of 196 young (age ≤ 45 year) female VWD patients, accounting for 31% of our study population. CONCLUSION: In young female VWD patients, we observed that low PAI-1 levels were associated with a higher bleeding score, which may partly explain the observed variability in bleeding phenotype in VWD patients.

Gynaecological and obstetrical bleeding in women with factor XI deficiency - a systematic review.

INTRODUCTION: Menstrual bleeding, pregnancy and delivery present an intrinsic haemostatic challenge to women with bleeding disorders such as factor XI (FXI) deficiency. AIM: To provide a systematic overview of studies on gynaecological and obstetrical bleeding problems in women with FXI deficiency. METHODS: We searched MEDLINE, EMBASE and the Cochrane library for studies that present original data on the incidence of and treatment options for gynaecological and obstetrical bleeding in FXI-deficient women. RESULTS: We identified 27 studies, including a total of 372 women with FXI deficiency. All studies were observational, no interventional treatment studies were found. Most patients had a mild deficiency (FXI ≥ 20 IU dL-1 ). Heavy menstrual bleeding (HMB) was reported in 7-67%. In 7/19 (37%) women who underwent gynaecological procedures, a bleeding complication occurred, including in 2/7 hysterectomies (29%). About 3-20% of reported pregnancies ended in a miscarriage; of these miscarriages 0-25% (4/23 miscarriages) were complicated by bleeding. Terminations of pregnancies (TOP) were complicated by bleeding in 4 out of 11 cases (36%). In 90 out of 498 (18%) deliveries a postpartum haemorrhage (PPH) was reported, ranging from 0 to 50% in individual studies. In 21% (66/321) of deliveries, prophylaxis was given. This was associated with 9% (6/66) PPH, compared to 19% in deliveries without prophylaxis (84/432). Epidural analgesia was performed without complications in 44 patients. CONCLUSION: Women with FXI deficiency have a clearly increased risk of HMB, and of bleeding complications after miscarriage, TOP and delivery. No high quality data are available regarding prophylactic treatment.

Facilitating the implementation of pharmacokinetic-guided dosing of prophylaxis in haemophilia care by discrete choice experiment.

INTRODUCTION: Patients', parents' and providers' preferences with regard to medical innovations may have a major impact on their implementation. AIM: To evaluate barriers and facilitators for individualized pharmacokinetic (PK)-guided dosing of prophylaxis in haemophilia patients, parents of young patients, and treating professionals by discrete choice experiment (DCE) questionnaire. PATIENTS/METHODS: The study population consisted of patients with haemophilia currently or previously on prophylactic treatment with factor concentrate (n = 114), parents of patients aged 12-18 years (n = 19) and haemophilia professionals (n = 91). DCE data analysis was performed, taking preference heterogeneity into account. RESULTS: Overall, patients and parents, and especially professionals were inclined to opt for PK-guided dosing of prophylaxis. In addition, if bleeding was consequently reduced, more frequent infusions were acceptable. However, daily dosing remained an important barrier for all involved. 'Reduction of costs for society' was a facilitator for implementation in all groups. CONCLUSIONS: To achieve implementation of individualized PK-guided dosing of prophylaxis in haemophilia, reduction of bleeding risk and reduction of costs for society should be actively discussed as they are motivating for implementation; daily dosing is still reported to be a barrier for all groups. The knowledge of these preferences will enlarge support for this innovation, and aid in the drafting of implementable guidelines and information brochures for patients, parents and professionals.

Joint surgery in von Willebrand disease: a multicentre cross-sectional study.

BACKGROUND: Joint bleeds are reported by 23% of von Willebrand disease (VWD) patients and associated with orthopaedic surgery. Limited data are available on joint surgery in VWD. AIM: To assess the prevalence, indications, management and complications of joint surgery in VWD patients. METHODS: 804 VWD patients with historically lowest von Willebrand factor (VWF) activity ≤30 U dL-1 completed a questionnaire on joint bleeds, joint damage and orthopaedic surgery. We retrieved additional medical file data of patients who underwent surgery on large joints (shoulder, elbow, hip, knee or ankle). RESULTS: 116 out of 804 patients (14%) reported large joint surgery. Compared to VWD patients without previous orthopaedic surgery, these 116 patients reported more frequently a history of joint bleeds and joint damage (41% vs. 20%, P < 0.001 and 61% vs. 20%, P < 0.001). Medical file data on 126 large joint surgeries in 79 VWD patients revealed that this surgery was associated with joint damage due to prior joint bleeds in 24% of the procedures. Preoperative clotting factor correction (CFC) to prevent bleeding was administered in most cases (81%). Documentation on postoperative bleeding was found in 23 surgeries (18%). CONCLUSIONS: Large joint surgery is reported by 14% of VWD patients, related to joint bleeds in 24% and seems associated with bleeding complications frequently despite perioperative CFC.

Continuous infusion of recombinant factor VIII formulated with sucrose in surgery: non-interventional, observational study in patients with severe haemophilia A.

In haemophilia A, continuous infusion (CI) of FVIII perioperatively provides a more constant FVIII level than conventional bolus injections, avoiding low trough levels that could increase bleeding risk. Due to the low number of surgical cases in clinical trials, especially in haemophilia, more information on the clinical practice of CI from observational studies is helpful. We aimed to evaluate the effectiveness and safety of CI with recombinant factor VIII formulated with sucrose (rFVIII-FS) in a typical surgery practice setting. This was a non-interventional study in 12 centres. Patients with severe haemophilia A who received rFVIII-FS by CI during and after surgery were included in this study if they had more than 150 exposure days (EDs) to any FVIII product and had no history of inhibitors before CI. Patients were observed during the entire course of CI, with monitoring up to 3 months thereafter. Twenty-five patients with 28 surgeries were included in the analysis. Median age was 51.7 (range 10-75). Most (75%; 21/25) patients underwent orthopaedic surgeries. The median dose of rFVIII-FS consumed during CI was 376 IU kg(-1) (range 157.9-3605.6 IU kg(-1)) with a greater median dose for orthopaedic surgeries (424.0 IU kg(-1)) compared to non-orthopaedic surgeries (278.5 IU kg(-1)). 95% of all FVIII measurements (214/224) were on target. Efficacy and tolerability were rated as good/excellent in 89.3% (25/28) of surgeries. No inhibitors were observed during or after surgery. This study demonstrates the effectiveness of CI with rFVIII-FS during surgery in patients with severe haemophilia A in a clinical practice setting.

Joint bleeds in von Willebrand disease patients have significant impact on quality of life and joint integrity: a cross-sectional study.

BACKGROUND: Joint bleeds (JB) are reported in a minority of patients with von Willebrand disease (VWD) but may lead to structural joint damage. Prevalence, severity and impact of JB in VWD are largely unknown. OBJECTIVES: The aim of this study was to assess JB prevalence, onset, treatment and impact on health-related quality of life (HR-QoL) and joint integrity in moderate and severe VWD. METHODS: In the Willebrand in the Netherlands study 804 moderate and severe VWD patients [von Willebrand factor (VWF) activity ≤30U dL(-1)] completed a questionnaire on occurrence, sites and consequences of JB. To analyse JB number, onset, treatment and impact on joint integrity we additionally performed a patient-control study on medical file data comparing patients with JB to age, gender, factor VIII (FVIII)- and VWF activity matched VWD patients without JB. RESULTS: Of all VWD patients 23% (184/804) self-reported JB. These 184 patients reported joint damage more often (54% vs. 18%, P < 0.001) and had lower HR-QoL (SF36, P < 0.05) compared to VWD patients not reporting JB. Of 55 patients with available JB data, 65% had the first JB before age 16. These 55 patients used more clotting factor concentrate (CFC; median dose 43 vs. 0 IE FVIII kg(-1) year(-1) , P < 0.001), more often had X-ray joint damage (44% vs. 11%, P = 0.001] and chronic joint pain (44% vs. 18%, P = 0.008) compared to 55 control VWD patients without JB. CONCLUSION: In conclusion, joint bleeds are reported by 23% of moderate and severe VWD patients, mostly start in childhood, are associated with more CFC use, joint pain, lower HR-QoL and significantly more radiological and self-reported joint damage.