Local density dependent potentials for an underlying van der Waals equation of state: A simulation and density functional theory analysis.

There is an ever increasing use of local density dependent potentials in the mesoscale modeling of complex fluids. Questions remain, though, about the dependence of the thermodynamic and structural properties of such systems on the cutoff distance used to calculate these local densities. These questions are particularly acute when it comes to the stability and structure of the vapor/liquid interface. In this article, we consider local density dependent potentials derived from an underlying van der Waals equation of state. We use simulation and density functional theory to examine how the bulk thermodynamic and interfacial properties vary with the cutoff distance, rc, used to calculate the local densities. We show quantitatively how the simulation results for bulk thermodynamic properties and vapor-liquid equilibrium approach the van der Waals limit as rc increases and demonstrate a scaling law for the radial distribution function in the large rc limit. We show that the vapor-liquid interface is stable with a well-defined surface tension and that the interfacial density profile is oscillatory, except for temperatures close to critical. Finally, we show that in the large rc limit, the interfacial tension is proportional to rc and, therefore, unlike the bulk thermodynamic properties, does not approach a constant value as rc increases. We believe that these results give new insights into the properties of local density dependent potentials, in particular their unusual interfacial behavior, which is relevant for modeling complex fluids in soft matter.

Association between burnout and wellness culture among emergency medicine providers

Objective@#Burnout is a common occurrence among healthcare providers and has been associated with provider wellness culture. However, this association has not been extensively studied among emergency medicine (EM) providers. We aim to determine the association between EM provider burnout and their culture of wellness, and to elicit the independent wellness culture domains most predictive of burnout prevention. @*Methods@#This was a multi-center observational study. We enrolled EM physicians and advanced practice providers from sixteen different emergency departments (EDs). Provider wellness culture and burnout surveys were performed. The wellness culture domains included in this study are personal/organizational value alignment, provider appreciation, leadership quality, self-controlled scheduling, peer support, and family support. Correlations between each wellness culture domain and burnout were analyzed by Pearson correlation co-efficiency, and their associations were measured by multivariate logistic regression with adjustments of other confounders. @*Results@#A total of 242 ED provider surveys were entered for final analysis. The overall burnout rate was 54% (130/242). Moderate correlations were found between burnout and two wellness culture domains (value alignment: r=-0.43, P<0.001 and provider appreciation: r=-0.49, P<0.001). The adjusted odds ratio of provider appreciation associated with burnout was 0.44 (95% confidence interval, 0.25–0.77; P=0.004), adjusted odds ratio of family support was 0.67 (95% confidence interval, 0.48–0.95; P=0.025). @*Conclusion@#ED providers have a relatively high burnout rate. Provider burnout might have certain associations with wellness culture domains. Provider appreciation and family support seem to play important roles in burnout protection.

Association between burnout and wellness culture among emergency medicine providers

Objective@#Burnout is a common occurrence among healthcare providers and has been associated with provider wellness culture. However, this association has not been extensively studied among emergency medicine (EM) providers. We aim to determine the association between EM provider burnout and their culture of wellness, and to elicit the independent wellness culture domains most predictive of burnout prevention. @*Methods@#This was a multi-center observational study. We enrolled EM physicians and advanced practice providers from sixteen different emergency departments (EDs). Provider wellness culture and burnout surveys were performed. The wellness culture domains included in this study are personal/organizational value alignment, provider appreciation, leadership quality, self-controlled scheduling, peer support, and family support. Correlations between each wellness culture domain and burnout were analyzed by Pearson correlation co-efficiency, and their associations were measured by multivariate logistic regression with adjustments of other confounders. @*Results@#A total of 242 ED provider surveys were entered for final analysis. The overall burnout rate was 54% (130/242). Moderate correlations were found between burnout and two wellness culture domains (value alignment: r=-0.43, P<0.001 and provider appreciation: r=-0.49, P<0.001). The adjusted odds ratio of provider appreciation associated with burnout was 0.44 (95% confidence interval, 0.25–0.77; P=0.004), adjusted odds ratio of family support was 0.67 (95% confidence interval, 0.48–0.95; P=0.025). @*Conclusion@#ED providers have a relatively high burnout rate. Provider burnout might have certain associations with wellness culture domains. Provider appreciation and family support seem to play important roles in burnout protection.

Reduced Thermodynamic Description of Phase Separation in a Quasi-One-Dimensional Granular Gas.

We describe simulations of a quasi-one-dimensional, vibrated granular gas which exhibits an apparent phase separation into a liquidlike phase and a gaslike phase. In thermal equilibrium, such a phase separation in one dimension is prohibited by entropic considerations. We propose that the granular gas minimizes a function of the conserved mechanical variables alone: the particle number and volume. Simulations in small cells can be used to extract the equation of state and predict the coexisting pressure and densities, as confirmation of the minimization principle. Fluctuations in the system manifest themselves as persistent density waves but they do not destroy the phase-separated state.

Controversies in the diagnosis of Type 1 von Willebrand disease.

von Willebrand disease (VWD) is the most common bleeding disorder. Type 1 VWD represents the majority of cases and results from a partial quantitative deficiency of von Willebrand factor (VWF). The diagnosis of Type 1 VWD presents many challenges, despite there being three established diagnostic criteria: a personal history of mucocutaneous bleeding, a family history and low VWF levels. These criteria do not always coexist, and there is great overlap of clinical phenotypes and laboratory parameters between healthy individuals and those with VWD. Mild bleeding symptoms can have any number of causes and bleeding is commonly reported in the general population. VWF levels do not always correlate with bleeding symptoms and can be variable between affected family members. Additionally, VWF levels vary widely as a result of both genetic and non-genetic influences. Perhaps the greatest current controversy in the diagnosis of Type 1 VWD is that there is no consensus laboratory cut-off for the diagnosis, raising concern about both over- and under-diagnosis. Ongoing studies are addressing these issues by clarifying the underlying pathogenesis of the disease, as well as the natural history and the risk of future bleeding in those with the diagnosis.

Evaluation of the utility of the ISTH-BAT in haemophilia carriers: a multinational study.

INTRODUCTION: There has been increasing recognition in recent years that female carriers of haemophilia manifest abnormal bleeding; however, data on the use of bleeding assessment tools in this population are lacking. AIM: Our objective was to validate the ISTH-BAT in haemophilia carriers to describe bleeding symptoms and allow for comparisons with factor levels and other patient groups. METHODS: This was a prospective, observational, cross-sectional study performed by members of Global Emerging HEmostasis Panel (GEHEP). Unselected consecutive haemophilia carriers were recruited and a CRF and the ISTH-BAT were completed by study personnel. RESULTS: A total of 168 haemophilia carriers were enrolled: 155 haemophilia A and 13 haemophilia B. The mean age was 40 years (range: 20-82). Carriers had higher mean bleeding scores (BS) compared with age-matched controls (n = 46; 5.7 vs. 1.43; P < 0.0001) and Type 3 VWD OC (n = 32; 3.0; P = 0.009), but lower BS compared with women with Type 1 VWD (n = 83; 8.7; P < 0.0001). Fifteen carriers reported haemarthrosis, and of those six had normal FVIII/FIX levels. There was a significant but weak negative correlation between BS and factor level (Spearman's r2  = -0.36, P < 0.001). CONCLUSION: Our results show that haemophilia carriers experience abnormal bleeding, including haemarthrosis. Overall, BS in women with Type 1 VWD > haemophilia carriers > Type 3 VWD OC > controls. Understanding the performance of the ISTH-BAT in this population is a critical step in future research aimed at investigating the underlying pathophysiology of abnormal bleeding, with the ultimate goal of optimizing treatment.

Histones link inflammation and thrombosis through the induction of Weibel-Palade body exocytosis.

Essentials Dysregulated DNA and histone release can promote pathological immunothrombosis. Weibel-Palade bodies (WPBs) are sentinel-like organelles that respond to proinflammatory stimuli. Histones induce WPB exocytosis in a caspase, calcium and charge-dependent mechanism. A targetable axis may exist between DNA/histones and WPBs in inflammation and immunothrombosis. SUMMARY: Background Damage-associated molecular patterns (DAMPs), including molecules such as DNA and histones, are released into the blood following cell death. DAMPs promote a procoagulant phenotype through enhancement of thrombin generation and platelet activation, thereby contributing to immunothrombosis. Weibel-Palade bodies (WPBs) are dynamic endothelial cell organelles that contain procoagulant and proinflammatory mediators, such as von Willebrand factor (VWF), and are released in response to cell stresses. VWF mediates platelet adhesion and aggregation, and has been implicated as a procoagulant component of the innate immune response. Objective To determine the influence of histones and DNA on WPB release, and characterize their association in models of inflammation. Methods We treated C57BL/6J mice and cultured endothelial cells with histones (unfractionated, lysine-rich or arginine-rich) and DNA, and measured WPB exocytosis. We used inhibitors to determine a mechanism of histone-induced WPB release in vitro. We characterized the release of DAMPs and WPBs in response to acute and chronic inflammation in human and murine models. Results and conclusions Histones, but not DNA, induced the release of VWF (1.46-fold) from WBPs and caused thrombocytopenia (0.74-fold), which impaired arterial thrombus formation in mice. Histones induced WPB release from endothelial cells in a caspase-dependent, calcium-dependent and charge-dependent manner, and promoted platelet capture in a flow chamber model of VWF-platelet string formation. The levels of DAMPs and WPB-released proteins were elevated during inflammation, and were positively correlated in chronic inflammation. These studies showed that DAMPs can regulate the function and level of VWF by inducing its release from endothelial WPBs. This DAMP-WPB axis may propagate immunothrombosis associated with inflammation.

The minimization of mechanical work in vibrated granular matter.

Experiments and computer simulations are carried out to investigate phase separation in a granular gas under vibration. The densities of the dilute and the dense phase are found to follow a lever rule and obey an equation of state. Here we show that the Maxwell equal-areas construction predicts the coexisting pressure and binodal densities remarkably well, even though the system is far from thermal equilibrium. This construction can be linked to the minimization of mechanical work associated with density fluctuations without invoking any concept related to equilibrium-like free energies.

Measures of trainee performance in advanced endoscopy: A systematic review.

INTRODUCTION: The diversity, technical skills required, and risk inherent to advanced endoscopy techniques all contribute to complex training curricula and steep learning curves. Since trainees develop endoscopy skills at different rates, there has been a shift towards competency-based training and certification. Validated endoscopy performance measures for trainees are, therefore, necessary. The aim of this systematic review was to describe and critically assess the existing evidence regarding measures of performance for trainees in advanced endoscopy. METHODS: A systematic review of the literature from January 1980 to January 2016 was carried out using the MEDLINE, EMBASE, CENTRAL, and ISI Web of knowledge databases. MeSH terms related to 'advanced endoscopy' and 'performance' were applied to a highly sensitive search strategy. The main outcomes were face, content, and construct validity, as well as reliability. RESULTS: The literature search yielded 1,662 studies and 77 met the inclusion criteria after abstract and full-text review (endoscopic retrograde cholangiopancreatography (ERCP)=23, endoscopic ultrasound (EUS)=30, colonoscopic polypectomy (CP)=11, balloon-assisted enteroscopy (BAE)=7, luminal stenting=3, radiofrequency ablation (RFA)=2, and endoscopic muscosal resection (EMR)=1). Good validity and reliability were found for measurement tools of overall performance in ERCP, EUS and CP, with applications for both patient-based and simulator training models. A number of specific technical skills were also shown to be valid measures of performance. These include: selective biliary cannulation, sphincterotomy, biliary stent placement, stone extraction and procedure time for ERCP; pancreatic solid mass T-staging, EUS-guided fine needle aspiration (EUS-FNA) procedure time, number of EUS-FNA passes and puncture precision for EUS; procedure time and en bloc resection rate for CP; retrograde fluoroscopy time for BAE; and mean number of endoscopy sessions required to achieve complete eradication of intestinal metaplasia (CIEM) for RFA. The evidence for EMR and luminal stenting is of insufficient quality to make recommendations. CONCLUSIONS: We have identified multiple valid and readily available performance measures for advanced endoscopy trainees for ERCP, EUS, CP, BAE and RFA procedures. These tools should be considered in advanced endoscopy training programs wishing to move away from apprenticeship-based training and towards competency-based learning with the help of patient-based and simulator tools.

Generation and optimization of the self-administered bleeding assessment tool and its validation as a screening test for von Willebrand disease.

INTRODUCTION/AIM: Our aim was to generate, optimize and validate a self-administered bleeding assessment tool (self-BAT) for von Willebrand disease (VWD). METHODS: In Phase 1, medical terminology in the expert-administered International Society on Thrombosis and Haemostasis (ISTH)-BAT was converted into a Grade 4 reading level to produce the first version of the Self-BAT which was then optimized to ensure agreement with the ISTH-BAT. In Phase 2, the normal range of bleeding scores (BSs) was determined and test-retest reliability analysed. In Phase 3, the optimized Self-BAT was tested as a screening tool for first time referrals to the Haematology clinic. RESULTS: Bleeding score from the final optimized version of the Self-BAT showed an excellent intra-class correlation coefficient (ICC) of 0.87 with ISTH-BAT BS in Phase 1. In Phase 2, the normal range of BSs for the optimized Self-BAT was determined to be 0 to +5 for females and 0 to +3 for males and excellent test-retest reliability was shown (ICC = 0.95). In Phase 3, we showed that a positive Self-BAT BS (≥6 for females, ≥4 for males) has a sensitivity of 78%, specificity of 23%, positive predictive value (PPV) of 0.15 and negative predictive value (NPV) of 0.86 for VWD; these figures improved when just the females were analysed; sensitivity of 100%, specificity of 21%, PPV = 0.17 and NPV = 1.0. CONCLUSION: We show an optimized Self-BAT can generate comparable BS to the expert-administered ISTH-BAT and is a reliable, effective screening tool to incorporate into the assessment of individuals, particularly women, referred for a possible bleeding disorder.

Changes in von Willebrand factor level and von Willebrand activity with age in type 1 von Willebrand disease.

In a normal population, VWF plasma levels (VWF:Ag) and VWF activity (VWF:RCo) increase by approximately 0.17 and 0.15 IU mL(-1) per decade, but the influence of age is unknown in patients with type 1 von Willebrand disease (VWD). In a retrospective cohort study, the medical records of 31 type 1 VWD patients over the age of 30, who had been followed for ≥5 years, were reviewed for baseline clinical data and previously performed VWF:Ag, VWF:RCo and factor VIII levels ( FVIII: C). VWF multimer analysis was normal in 28/31 cases performed. Mean age at diagnosis was 33 (range 16-60 years), and duration of follow-up ranged from 5 to 26 years (mean 11 years). Patients had 2-10 time points of VWD testing (mean of 5.2). The mean VWF:Ag, VWF:RCo and FVIII: C at time of diagnosis were 0.44 IU mL(-1) 0.34 IU mL(-1) and 0.75 IU mL(-1) . At last follow-up, the mean VWF:Ag, VWF:RCo and FVIII: C were significantly increased to 0.71 IU L(-1) , 0.56 IU mL(-1) and 0.90 IU mL(-1) (P ≤ 0.001, <0.001, and 0.0081 respectively). Here 18/31 patients had VWF:Ag, VWF:RCo and FVIII: C levels that increased into the normal range. The rate of change in VWF:Ag, VWF:RCo and FVIII was 0.30 IU mL(-1) (0.21-0.39, CI 95%, P < 0.0001), 0.20 IU mL(-1) per decade (0.13-0.27, CI 95%, P = 0.0001) and 0.20 IU mL(-1) (0.11-0.29, CI 95%, P = 0.0011). Patients with type 1 VWD experience age-related increases to VWF:Ag and VWF:RCo which can result in normalization of VWF levels. Further studies are required to determine if the bleeding phenotype resolves with the increases in VWF:Ag and VWF:RCo levels.

Normal range of bleeding scores for the ISTH-BAT: adult and pediatric data from the merging project.

Bleeding Assessment Tools (BATs) have been developed to aid in the standardized evaluation of bleeding symptoms. The Vicenza Bleeding Questionnaire (BQ), published in 2005, established a common framework and scoring key that has undergone subsequent modification over the years, culminating in the publication of the ISTH-BAT in 2010. Understanding the normal range of bleeding scores is critical when assessing the utility of a BAT. Within the context of The Merging Project, a bioinformatics system was created to facilitate the merging of legacy data derived from four different (but all Vicenza-based) BATs; the MCMDM1-VWD BQ, the Condensed MCMDM-1VWD BQ, the Pediatric Bleeding Questionnaire and the ISTH-BAT. Data from 1040 normal adults and 328 children were included in the final analysis, which showed that the normal range is 0-3 for adult males, 0-5 for adult females and 0-2 in children for both males and females. Therefore, the cut-off for a positive or abnormal BS is ≥4 in adult males, ≥6 in adult females and ≥3 in children. This information can now be used to objectively assess bleeding symptoms as normal or abnormal in future studies.

The molecular characterization of von Willebrand disease: good in parts.

Since the cloning of the gene that encodes von Willebrand factor (VWF), 27 years ago, significant progress has been made in our understanding of the molecular basis of the most common inherited bleeding disorder, von Willebrand disease (VWD). The molecular pathology of this condition represents a range of genetic mechanisms, some of which are now very well characterized, and others that are still under investigation. In general, our knowledge of the molecular basis of type 2 and 3 VWD is now well advanced, and in some instances this information is being used to enhance clinical management. In contrast, our understanding of the molecular pathogenesis of the most common form of VWD, type 1 disease, is still at an early stage, with preliminary evidence that this phenotype involves a complex interplay between environmental factors and the influence of genetic variability both within and outside of the VWF locus.

Emergent surface tension in vibrated, noncohesive granular media.

We describe experiments and simulations carried out to investigate spinodal decomposition in a vibrated, dry granular system. The dynamics is found to be similar to that of systems evolving under curvature-driven diffusion, which suggests the presence of an effective surface tension. By studying quasi-2D droplets in the steady state, we find behavior consistent with Laplace's equation, demonstrating the existence of an actual surface tension. Detailed measurements of the pressure tensor in the interfacial region show that the surface tension results predominantly from an anisotropy in the kinetic energy part of the pressure tensor, in contrast to thermodynamic systems where it arises from either the attractive interaction between particles or entropic considerations.

Liquid-gas phase separation in confined vibrated dry granular matter.

A new phase transition is observed experimentally in a dry granular gas subject to vertical vibration between two horizontal plates. Molecular dynamics simulations of this system allow us to investigate the observed phase separation in detail. We find a high-density, low temperature liquid, coexisting with a low-density, high temperature gas moving coherently. The importance of the coherent motion for phase separation is investigated using frequency modulation.

Expanded phenotype-genotype correlations in a pediatric population with type 1 von Willebrand disease.

BACKGROUND: Recent phenotype-genotype studies have provided valuable insights into the pathophysiology of type 1 von Willebrand disease (VWD); however, no study has examined an exclusively pediatric cohort. OBJECTIVES: To describe phenotype-genotype correlations in a selected pediatric cohort with a historical diagnosis of type 1 VWD, using first-degree family members as controls. METHODS: Comprehensive phenotypic assessment included standard assays of von Willebrand factor (VWF) level and function, bleeding score, desmopressin response, VWF propeptide (VWFpp) level, and platelet-derived VWF mRNA level. RESULTS: Fourteen VWF mutations were identified in 17 of 23 index cases (ICs) (aged 5-17 years), including four that were previously unreported (L60P, nt1658 insT, Q1388X, and C2237F). VWFpp levels were lower in ICs than in unaffected controls (median 49 vs. 86 U dL(-1) , P < 0.0001). A VWFpp/VWF antigen ratio of > 1.6 was observed in eight of nine ICs with a suboptimal response to desmopressin, including four of four with the R1205H (Vicenza) mutation (median 7.9), and three of four IC with the R1315C mutation (median 1.9). The R1315C mutation was also associated with a reduced absolute VWFpp level (median 32 U dL(-1) ), a previously unreported finding. The amount of platelet-derived VWF mRNA was significantly reduced in individuals with nonsense mutations. CONCLUSIONS: Increased VWF clearance and intracellular retention are important mechanisms underlying type 1 VWD in pediatric patients, concordant with the observations of larger, predominantly adult, cohort studies. Additionally, in some patients, nonsense-mediated decay of mutant mRNA transcripts may be contributory. Several mechanisms underlie the variable phenotype associated with the R1315C mutation. The potential utility of VWFpp as an independent marker of VWF biosynthesis and release warrants further research.

Quantitation of bleeding symptoms in children with von Willebrand disease: use of a standardized pediatric bleeding questionnaire.

SUMMARY BACKGROUND: Excessive bruising and mucocutaneous bleeding are frequent presenting symptoms in childhood. A detailed bleeding history can distinguish children who may have an inherited bleeding disorder from those who are normal. There is a lack of standardization of such history taking in pediatric practise. OBJECTIVES: To assess the performance of a Pediatric Bleeding Questionnaire (PBQ), an adaptation of a standardized adult bleeding questionnaire and score that includes pediatric-specific bleeding symptoms, in a cohort of children with von Willebrand disease (VWD). PATIENTS/METHODS: Bleeding scores were determined by interview, for children with a previous diagnosis of VWD and a control group of unaffected siblings. RESULTS: Bleeding scores were obtained for 100 children with VWD, median age 10.9 years (range, 0.8-17.8 years), and 21 unaffected siblings. Median bleeding score in children with VWD was 7.0 (range, 0-29) and in the control group was 0 (range, -1-2). Bleeding score varied within and between each VWD type: definite type 1, n = 40, median, 9.0 (range, 2-18); possible type 1, n = 38, median, 2.0 (0-15); type 2, n = 6, median, 14.0 (3-17); and type 3, n = 16, median, 12.0 (4-29). Bleeding scores in affected children correlated with age (Spearman's correlation coefficient, 0.35; P = 0.0004). The most frequent clinically significant bleeding symptoms were surgical bleeding, bleeding after tooth extraction and menorrhagia. Post-circumcision bleeding, cephalohematoma, macroscopic hematuria and umbilical stump bleeding were clinically significant in 32% (of circumcised males), 4%, 4% and 3% of children, respectively. CONCLUSIONS: The PBQ provides a standardized quantitation of bleeding severity in children with VWD.