A Patient-Specific Fracture Risk Assessment Tool for Femoral Bone Metastases:Using the Bone Strength (BOS) Score in Clinical Practice

Patients with femoral metastases are at risk of fracturing bones. It is important to prevent fractures in order to maintain mobility and quality of life. The BOne Strength (BOS) score is based on a computed tomography (CT)-based patient-specific finite element (FE) computer model that objectively calculates bone strength. In this pilot study, the added clinical value of the BOS score towards treatment-related decision making was assessed. In December 2019, the BOS score was implemented in four radiotherapy centers. The BOS scores and fracture risks of individual patients were calculated and returned to the physician to assist in treatment decisions. The physicians filled out a questionnaire, which was qualitatively analyzed. A follow-up to identify fractures and/or death was performed after six months. Until June 2021, 42 BOS scores were delivered (20 high, 9 moderate, and 13 low fracture risk). In 48%, the BOS score led to an adaptation of treatment plans. Physicians indicated that the BOS score provided objective insight into fracture risk, was reassuring for physicians and patients, and improved multidisciplinary discussions and shared decision making. In conclusion, the BOS score is an objective tool to assess fracture risk in femoral bone metastases and aids physicians and patients in making a more informed decision regarding the most appropriate treatment.</p

The effect of a daily quiz (TOPday) on self-confidence, enthusiasm, and test results for biomechanics

Many students in Biomedical Sciences have difficulty understanding biomechanics. In a second-year course, biomechanics is taught in the first week and examined at the end of the fourth week. Knowledge is retained longer if the subject material is repeated. However, how does one encourage students to repeat the subject matter? For this study, we developed ‘two opportunities to practice per day (TOPday)’, consisting of multiple-choice questions on biomechanics with immediate feedback, which were sent via e-mail. We investigated the effect of TOPday on self-confidence, enthusiasm, and test results for biomechanics. All second-year students (n = 95) received a TOPday of biomechanics on every regular course day with increasing difficulty during the course. At the end of the course, a non-anonymous questionnaire was conducted. The students were asked how many TOPday questions they completed (0–6 questions [group A]; 7–18 questions [group B]; 19–24 questions [group C]). Other questions included the appreciation for TOPday, and increase (no/yes) in self-confidence and enthusiasm for biomechanics. Seventy-eight students participated in the examination and completed the questionnaire. The appreciation for TOPday in group A (n = 14), B (n = 23) and C (n = 41) was 7.0 (95 % CI 6.5–7.5), 7.4 (95 % CI 7.0–7.8), and 7.9 (95 % CI 7.6–8.1), respectively (p < 0.01 between A and C). Of the students who actively participated (B and C), 91 and 80 % reported an increase in their self-confidence and enthusiasm, respectively, for biomechanics due to TOPday. In addition, they had a higher test result for biomechanics (p < 0.01) compared with those who did not actively participate (A). In conclusion, the teaching method ‘TOPday’ seems an effective way to encourage students to repeat the subject material, with the extra advantage that students are stimulated to keep on practising for the examination. The appreciation was high and there was a positive association between active participation, on the one hand, and self-confidence, enthusiasm, and test results for biomechanics on the other

The Use of a Daily Quiz" TOPday" as Supportive Learning Method for Medical Students

Medical students consider anatomy, neurology, and traumatology as difficult study topics. A recent study showed that the daily quiz ‘Two Opportunities to Practice per day (TOPday)’ positively supported biomedical students in analyzing and solving biomechanical problems. The main purpose of this study was to investigate the effect of TOPday on self-confidence, enthusiasm, and test results for the topics anatomy, neurology and traumatology. Second-year medical students were enrolled in a four-week course on the human skeletal system at the Radboudumc (n = 799). They were randomized over three topic groups (anatomy, neurology, and traumatology) and received TOPday quizzes on every course day. At the end of the course students filled in a non-anonymous questionnaire. Students highly appreciated TOPday (7.5±0.9) and this did not differ between groups (anatomy: 7.4±0.8; neurology: 7.4±1.1; traumatology: 7.5±0.8; P = 0.68). Many students reported that TOPday increased their self-confidence (65% of the students) and enthusiasm (69% of the students) for their topic. However, test results of the students did not improve. A potential explanation for the latter result may relate to the different cognitive processes that are required to study anatomy, neurology, and traumatology compared to biomechanics. In conclusion, appreciation, self-confidence and enthusiasm were positively associated with TOPday, but test results were not

Flecainide Is Associated With a Lower Incidence of Arrhythmic Events in a Large Cohort of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia

BACKGROUND: In severely affected patients with catecholaminergic polymorphic ventricular tachycardia, beta-blockers are often insufficiently protective. The purpose of this study was to evaluate whether flecainide is associated with a lower incidence of arrhythmic events (AEs) when added to beta-blockers in a large cohort of patients with catecholaminergic polymorphic ventricular tachycardia. METHODS: From 2 international registries, this multicenter case cross-over study included patients with a clinical or genetic diagnosis of catecholaminergic polymorphic ventricular tachycardia in whom flecainide was added to beta-blocker therapy. The study period was defined as the period in which background therapy (ie, beta-blocker type [beta1-selective or nonselective]), left cardiac sympathetic denervation, and implantable cardioverter defibrillator treatment status, remained unchanged within individual patients and was divided into pre-flecainide and on-flecainide periods. The primary end point was AEs, defined as sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter defibrillator shock, and arrhythmic syncope. The association of flecainide with AE rates was assessed using a generalized linear mixed model assuming negative binomial distribution and random effects for patients. RESULTS: A total of 247 patients (123 [50%] females; median age at start of flecainide, 18 years [interquartile range, 14-29]; median flecainide dose, 2.2 mg/kg per day [interquartile range, 1.7-3.1]) were included. At baseline, all patients used a beta-blocker, 70 (28%) had an implantable cardioverter defibrillator, and 21 (9%) had a left cardiac sympathetic denervation. During a median pre-flecainide follow-up of 2.1 years (interquartile range, 0.4-7.2), 41 patients (17%) experienced 58 AEs (annual event rate, 5.6%). During a median on-flecainide follow-up of 2.9 years (interquartile range, 1.0-6.0), 23 patients (9%) experienced 38 AEs (annual event rate, 4.0%). There were significantly fewer AEs after initiation of flecainide (incidence rate ratio, 0.55 [95% CI, 0.38-0.83]; P=0.007). Among patients who were symptomatic before diagnosis or during the pre-flecainide period (n=167), flecainide was associated with significantly fewer AEs (incidence rate ratio, 0.49 [95% CI, 0.31-0.77]; P=0.002). Among patients with ≥1 AE on beta-blocker therapy (n=41), adding flecainide was also associated with significantly fewer AEs (incidence rate ratio, 0.25 [95% CI, 0.14-0.45]; P&lt;0.001). CONCLUSIONS: For patients with catecholaminergic polymorphic ventricular tachycardia, adding flecainide to beta-blocker therapy was associated with a lower incidence of AEs in the overall cohort, in symptomatic patients, and particularly in patients with breakthrough AEs while on beta-blocker therapy.</p

Flecainide Is Associated With a Lower Incidence of Arrhythmic Events in a Large Cohort of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia

BACKGROUND: In severely affected patients with catecholaminergic polymorphic ventricular tachycardia, beta-blockers are often insufficiently protective. The purpose of this study was to evaluate whether flecainide is associated with a lower incidence of arrhythmic events (AEs) when added to beta-blockers in a large cohort of patients with catecholaminergic polymorphic ventricular tachycardia. METHODS: From 2 international registries, this multicenter case cross-over study included patients with a clinical or genetic diagnosis of catecholaminergic polymorphic ventricular tachycardia in whom flecainide was added to beta-blocker therapy. The study period was defined as the period in which background therapy (ie, beta-blocker type [beta1-selective or nonselective]), left cardiac sympathetic denervation, and implantable cardioverter defibrillator treatment status, remained unchanged within individual patients and was divided into pre-flecainide and on-flecainide periods. The primary end point was AEs, defined as sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter defibrillator shock, and arrhythmic syncope. The association of flecainide with AE rates was assessed using a generalized linear mixed model assuming negative binomial distribution and random effects for patients. RESULTS: A total of 247 patients (123 [50%] females; median age at start of flecainide, 18 years [interquartile range, 14-29]; median flecainide dose, 2.2 mg/kg per day [interquartile range, 1.7-3.1]) were included. At baseline, all patients used a beta-blocker, 70 (28%) had an implantable cardioverter defibrillator, and 21 (9%) had a left cardiac sympathetic denervation. During a median pre-flecainide follow-up of 2.1 years (interquartile range, 0.4-7.2), 41 patients (17%) experienced 58 AEs (annual event rate, 5.6%). During a median on-flecainide follow-up of 2.9 years (interquartile range, 1.0-6.0), 23 patients (9%) experienced 38 AEs (annual event rate, 4.0%). There were significantly fewer AEs after initiation of flecainide (incidence rate ratio, 0.55 [95% CI, 0.38-0.83]; P=0.007). Among patients who were symptomatic before diagnosis or during the pre-flecainide period (n=167), flecainide was associated with significantly fewer AEs (incidence rate ratio, 0.49 [95% CI, 0.31-0.77]; P=0.002). Among patients with ≥1 AE on beta-blocker therapy (n=41), adding flecainide was also associated with significantly fewer AEs (incidence rate ratio, 0.25 [95% CI, 0.14-0.45]; P&lt;0.001). CONCLUSIONS: For patients with catecholaminergic polymorphic ventricular tachycardia, adding flecainide to beta-blocker therapy was associated with a lower incidence of AEs in the overall cohort, in symptomatic patients, and particularly in patients with breakthrough AEs while on beta-blocker therapy.</p

An International Multicenter Cohort Study on beta-Blockers for the Treatment of Symptomatic Children With Catecholaminergic Polymorphic Ventricular Tachycardia

Background: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. β-Blockers decrease this risk, but studies comparing individual β-blockers in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of β-blocker in a large cohort of symptomatic children with CPVT.Methods: From 2 international registries of patients with CPVT, RYR2 variant–carrying symptomatic children (defined as syncope or sudden cardiac arrest before β-blocker initiation and age at start of β-blocker therapy &lt;18 years), treated with a β-blocker were included. Cox regression analyses with time-dependent covariates for β-blockers and potential confounders were used to assess the hazard ratio (HR). The primary outcome was the first occurrence of sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter-defibrillator shock, or syncope. The secondary outcome was the first occurrence of any of the primary outcomes except syncope.Results: We included 329 patients (median age at diagnosis, 12 [interquartile range, 7–15] years, 35% females). Ninety-nine (30.1%) patients experienced the primary outcome and 74 (22.5%) experienced the secondary outcome during a median follow-up of 6.7 (interquartile range, 2.8–12.5) years. Two-hundred sixteen patients (66.0%) used a nonselective β-blocker (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a β1-selective β-blocker (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial β-blocker. Baseline characteristics did not differ. The HRs for both the primary and secondary outcomes were higher for β1-selective compared with nonselective β-blockers (HR, 2.04 [95% CI, 1.31–3.17]; and HR, 1.99 [95% CI, 1.20–3.30], respectively). When assessed separately, the HR for the primary outcome was higher for atenolol (HR, 2.68 [95% CI, 1.44–4.99]), bisoprolol (HR, 3.24 [95% CI, 1.47–7.18]), and metoprolol (HR, 2.18 [95% CI, 1.08–4.40]) compared with nadolol, but did not differ from propranolol. The HR of the secondary outcome was only higher in atenolol compared with nadolol (HR, 2.68 [95% CI, 1.30–5.55]).Conclusions: β1-selective β-blockers were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with nonselective β-blockers, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred β-blocker for treating symptomatic children with CPVT.</p

The Angio-Fibrotic Switch of VEGF and CTGF in Proliferative Diabetic Retinopathy

BACKGROUND: In proliferative diabetic retinopathy (PDR), vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) cause blindness by neovascularization and subsequent fibrosis, but their relative contribution to both processes is unknown. We hypothesize that the balance between levels of pro-angiogenic VEGF and pro-fibrotic CTGF regulates angiogenesis, the angio-fibrotic switch, and the resulting fibrosis and scarring. METHODS/PRINCIPAL FINDINGS: VEGF and CTGF were measured by ELISA in 68 vitreous samples of patients with proliferative DR (PDR, N = 32), macular hole (N = 13) or macular pucker (N = 23) and were related to clinical data, including degree of intra-ocular neovascularization and fibrosis. In addition, clinical cases of PDR (n = 4) were studied before and after pan-retinal photocoagulation and intra-vitreal injections with bevacizumab, an antibody against VEGF. Neovascularization and fibrosis in various degrees occurred almost exclusively in PDR patients. In PDR patients, vitreous CTGF levels were significantly associated with degree of fibrosis and with VEGF levels, but not with neovascularization, whereas VEGF levels were associated only with neovascularization. The ratio of CTGF and VEGF was the strongest predictor of degree of fibrosis. As predicted by these findings, patients with PDR demonstrated a temporary increase in intra-ocular fibrosis after anti-VEGF treatment or laser treatment. CONCLUSIONS/SIGNIFICANCE: CTGF is primarily a pro-fibrotic factor in the eye, and a shift in the balance between CTGF and VEGF is associated with the switch from angiogenesis to fibrosis in proliferative retinopathy

Nonlinear voxel-based finite element model for strength assessment of healthy and metastatic proximal femurs

Nonlinear finite element (FE) models can accurately quantify bone strength in healthy and metastatic femurs. However, their use in clinical practice is limited since state-of-the-art implementations using tetrahedral meshes involve a lot of manual work for which specific modelling software and engineering knowledge are required. Voxel-based meshes could enable the transition since they are robust and can be highly automated. Therefore, the aim of this work was to bridge the modelling gap between the tetrahedral and voxel-based approach. Specifically, we validated a nonlinear voxel-based FE method relative to experimental data from 20 femurs with and without artificial metastases that had been mechanically loaded until failure. CT scans of the femurs were segmented and automatically converted into a voxel-based mesh with hexahedral elements. Nonlinear material properties were implemented in an open-source linear voxel-based FE solver by adding an additional loop to the routine such that the material properties could be adapted after each increment. Bone strength, quantified as the maximum force in the force-displacement curve, was evaluated. The results were compared to a previously established nonlinear tetrahedral FE approach as well as to the experimentally measured bone strength. The voxel-based FE model predicted the experimental bone strength very well both for healthy (R2 = 0.90, RMSE = 0.88 kN) and metastatic femurs (R2 = 0.93, RMSE = 0.64 kN). The model precision and accuracy were very similar to the ones obtained with the tetrahedral model (R2 = 0.90/0.93, RMSE = 0.90/0.64 kN for intact/metastatic respectively). The more intuitive voxel-based meshes thus quantified macroscale femoral strength equally well as state-of-the-art tetrahedral models. The robustness, high level of automation and time-efficiency (< 30 min) of the implemented workflow offer great potential for developing FE models to improve fracture risk prediction in clinical practice.status: Published onlin