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Type 1 von Willebrand disease (VWD) is associated with a reduction in qualitatively normal von Willebrand factor (VWF). Current diagnostic guidelines only take into consideration the contribution of basal VWF levels, despite a lack of correlation with bleeding severity. Defects in stimulated VWF release, which occurs after hemostatic challenge, may contribute to bleeding in type 1 VWD, but the pathogenic mechanisms are poorly defined. In this study, a layered multiomic approach including messenger RNA (mRNA) and microRNA (miRNA) sequencing was used to evaluate transcriptome-wide differences between type 1 VWD- and control-derived endothelial colony forming cells (ECFCs) during basal and stimulated VWF release. ECFCs from 8 patients with type 1 VWD and 4 other patients were included in this study as controls. VWF protein analysis revealed heterogenous responses to stimulation among type 1 VWD and control ECFCs. During basal VWF release, 64 mRNAs and 7 miRNAs were differentially regulated between type 1 VWD and control ECFCs, and 65 putatively pathogenic miRNA-mRNA interactions were identified. During stimulated VWF release, 190 mRNAs and 5 mRNAs were differentially regulated between type 1 VWD and control ECFCs, and 110 putatively pathogenic miRNA-mRNA interactions were identified. Five gene ontology terms including coagulation, regulation of cell shape, and regulation of cell signaling were also differentially regulated in type 1 VWD ECFCs during stimulated release. To our knowledge, we have shown for the first time that transcriptome-wide differences exist between type 1 VWD and control ECFCs. These differences may contribute to bleeding in type 1 VWD, and further investigation may reveal novel biomarkers and therapeutic targets.

OBJECTIVE: To provide recommendations for management of patients presenting with elevated self-administered bleeding assessment tool (Self-BAT) scores or other bleeding symptoms in a primary care setting. SOURCES OF INFORMATION: Primary research sources, clinical review articles, and interviews with research staff, hematologists, and family physicians were used to create the poster tools and reference guide resources. MAIN MESSAGE: Recommendations to manage a patient with an elevated Self-BAT score or other bleeding symptoms include reviewing the results of the Self-BAT to clarify relevant symptoms, performing initial diagnostic laboratory tests, and doing basic symptom management. Clinical judgment should be used when determining whether referral to a hematologist is necessary, but referral should be considered if the bleeding score is abnormal or if initial management options are ineffective. Some bleeding symptoms warrant evaluation by a gastroenterologist, obstetrician-gynecologist, or otolaryngologist. CONCLUSION: Primary care providers should conduct a thorough review of the Self-BAT results and associated management recommendations when working with a patient presenting with an elevated score or other bleeding manifestations. A review consists of the clarification of relevant symptoms, appropriate initial laboratory workups, and patient education. Treatment options for symptom management should be explored while recognizing the threshold for referral to a hematologist.

OBJECTIF: Présenter des recommandations sur la prise en charge des patients qui ont obtenu des scores élevés avec l’outil d’autoévaluation des saignements (Self-BAT) ou qui présentent d’autres symptômes hémorragiques, en milieu de soins primaires. SOURCES DE L’INFORMATION: Des sources de recherche primaire, des articles de revues cliniques, et des entrevues avec du personnel de recherche, des hématologues et des médecins de famille ont servi à produire les ressources sous forme d’affiches et d’un guide de référence. MESSAGE PRINCIPAL: Parmi les recommandations sur la prise en charge d’un patient dont les scores au Self-BAT sont élevés ou qui présente d’autres symptômes hémorragiques figurent les suivantes : passer en revue les résultats du Self-BAT pour clarifier les symptômes pertinents, effectuer les tests diagnostiques de laboratoire initiaux et gérer les symptômes de base. Il faut se servir de son jugement clinique pour déterminer la nécessité d’une demande de consultation en hématologie, mais il y a lieu d’envisager une telle démarche si les scores liés aux saignements sont anormaux ou si les options de gestion initiales ne sont pas efficaces. Il est justifié que certains symptômes hémorragiques soient évalués par un gastroentérologue, un obstétricien-gynécologue ou un otorhinolaryngologiste. CONCLUSION: Les professionnels des soins primaires devraient examiner rigoureusement les résultats du Self-BAT et les recommandations de prise en charge connexes dans le cas d’un patient qui a un score élevé ou présente d’autres manifestations hémorragiques. L’examen comprend la clarification des symptômes pertinents, les analyses de laboratoire pertinentes laboratoire et l’éducation du patient. Les options thérapeutiques pour la gestion des symptômes devraient être envisagées, tout en le reconnaissant lorsqu’il s’impose de demander une consultation en hématologie.

At a population level, there is a poor understanding of the incidence and pre-disposing risk factors of postpartum haemorrhage (PPH) among women with inherited bleeding disorders (IBD).To determine the incidence of PPH, and identify maternal factors associated with risk of PPH among women with IBD.We conducted a retrospective cohort study using data housed within ICES (formerly known as the Institute for Clinical Evaluative Sciences). The cohort included women with an in-hospital, live or stillborn delivery, between January 2014 and December 2019. The primary outcome was PPH (identified by ICD-10 code O72). PPH incidence and risk factors were compared between women with and without IBD. Temporal trends were assessed using the Cochrane-Armitage test. Between group differences were assessed using standardised differences (std. difference).Total 601,773 women were included; 2002 (.33%) had an IBD diagnosis. PPH incidence was 1.5 times higher (7.3 vs. 4.9 cases/100 deliveries, std. difference .1) among women with IBD compared to women without. Women with IBD were slightly older (31.7 vs. 30.7 years), had higher rates of hypertension, previous PPH, and induction of labour. Women with IBD were more frequently diagnosed with anaemia (4.8% vs. 1.8%; std difference .17) and had lower haemoglobin levels at admission for delivery compared to women without IBD.This study contributes to the literature regarding obstetric bleeding among women with IBD, showing that anaemia at delivery may be an important risk factor for PPH. Given their predisposition to anaemia, clarifying this relationship will optimise management and outcomes.

BACKGROUND: Heavy menstrual bleeding (HMB) affects a significant number of women with bleeding disorders and has a negative impact on their quality of life. OBJECTIVE: This retrospective study examined the management of patients with inherited bleeding disorders who used medical treatments, alone or in combination, for HMB. METHODS: Chart review was performed on women attending the Women with Bleeding Disorders Clinic in Kingston, Ontario, between 2005 and 2017. Data collected included patient demographics, the reason for presentation and diagnosis, medical history, treatments, and patient satisfaction. RESULTS: One hundred nine women were included in this cohort. Of these, only 74 (68%) were satisfied with medical management, and only 18 (17%) with first-line therapy. Treatments included combined contraceptives (oral pill, transdermal patch, and vaginal ring), progesterone-only pills, tranexamic acid, 52-mg levonorgestrel intrauterine system (LIUS), depomedroxyprogesterone acetate, and desmopressin, either alone or in combination. Satisfactory control of HMB occurred most often with the LIUS. CONCLUSION: In this cohort, managed in a tertiary care Women with Bleeding Disorders Clinic, only 68% of patients had successful control of HMB with medical treatment, and a minority were satisfied with first-line therapy. These data clearly highlight the need for additional research, including treatment approaches and novel therapies for this population.

Clinicians often order the international normalized ratio (INR) and activated partial thromboplastin time (APTT) to evaluate for the possibility of inherited bleeding disorders despite sensitivities and specificities of 1%-2%. The most accurate tool to evaluate for bleeding disorders is a validated bleeding assessment tool (BAT). Our aim was to reduce coagulation testing by50% in a large family practice in Ontario, Canada.We conducted an implementation study from May 2016 to February 2020. Iterative interventions included introduction of a validated BAT into the electronic medical record (EMR); removal of the APTT as a prepopulated selection from the laboratory requisition; and education targeting family medicine teams and laboratory personnel. The primary outcome was the rate of pre- and post-APTT testing. Creatinine testing was the control. Data were analyzed via an interrupted time series analysis using Stata 13.Immediately following education of the laboratory personnel on coagulation testing, the APTT rate level dropped by 1.26 tests per 100 patient visits per month (Multidisciplinary, iterative interventions reduced APTT testing and enabled the use of BATs to guide hematology referrals in a large family practice.

BACKGROUND: von Willebrand Factor (VWF) is synthesized by vascular endothelial cells and megakaryocytes. The VWF propeptide is critical for multimerization and acts as an intra-molecular chaperone for mature VWF in sorting to its storage organelles, Weibel-Palade bodies (WPBs). In the Canadian Type 3 VWD study, almost half of the identified variants were in the VWF propeptide and these were associated with an increased bleeding phenotype. OBJECTIVE: To investigate VWF propeptide variants that cause quantitative von Willebrand disease (VWD) by utilizing patient-derived endothelial colony-forming cells (ECFCs). PATIENTS/METHODS: ECFCs were isolated from five Type 3 VWD patients from four families with the following variants: 1) homozygous p.Asp75_Gly178del (deletion of exons 4 and 5 deletion; Ex4-5del); 2) homozygous p.Cys633Arg; 3) homozygous p.Arg273Trp, and 4) p.Pro293Glnfs*164 and p.Gln419* inherited in the compound heterozygous state. Additionally, ECFCs were isolated from six family members (two Type 1 VWD, four unaffected). RESULTS: ECFCs from the Type 3 patient with the compound heterozygous genotype exhibited a true null VWF cellular phenotype, with negligible VWF detected. In contrast, the other three propeptide variants presented a similar expression pattern in homozygous ECFCs where VWF was synthesized but not packaged in WPBs, and variant VWF had an increased association with the endoplasmic reticulum (ER) marker, protein disulfide-isomerase (PDI), indicating an ER-retention phenotype. The biosynthetic phenotype was similar but to a lesser degree in heterozygous ECFCs expressing the non-null variants. CONCLUSION: This study further elucidates the importance of the VWF propeptide in the VWD phenotype using patient-derived cells.

Background Von Willebrand Disease (VWD) is a common inherited bleeding disorder. Patients with VWD suffering from severe bleeding may benefit from the use of secondary long-term prophylaxis. Aim Systematically summarize the evidence on the clinical outcomes of secondary long-term prophylaxis in patients with VWD and severe recurrent bleedings. Methods We searched Medline and EMBASE through October 2019 for relevant randomized clinical trials (RCTs) and comparative observational studies (OS) assessing the effects of secondary long-term prophylaxis in patients with VWD. We used Cochrane Risk of Bias (RoB) tool and the RoB for Non-Randomized Studies of interventions (ROBINS-I) tool to assess the quality of the included studies. We conducted random-effects meta-analyses and assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Results We included 12 studies. Evidence from one placebo controlled RCT suggested that VWD prophylaxis as compared to no prophylaxis reduced the rate of bleeding episodes (Rate ratio [RR], .24; 95% confidence interval [CI], .17–.35; low certainty evidence), and of epistaxis (RR, .38; 95%CI, .21–.67; moderate certainty evidence), and may increase serious adverse events RR 2.73 (95%CI .12–59.57; low certainty). Evidence from four before-and-after studies in which researchers reported comparative data suggested that VWD prophylaxis reduced the rate of bleeding (RR .34; 95%CI, .25–.46; very low certainty evidence). Conclusion VWD prophylaxis treatment seems to reduce the risk of spontaneous bleeding, epistaxis, and hospitalizations. More RCTs should be conducted to increase the certainty in these benefits.

von Willebrand Disease (VWD) is associated with significant morbidity because of excessive bleeding. Early diagnosis and treatment are important to prevent and treat these symptoms. We systematically reviewed the accuracy of any von Willebrand factor (VWF) activity assay in the diagnosis and classification of patients for VWD. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 and the certainty of evidence using the GRADE framework. We pooled estimates of sensitivity and specificity. The review included 77 studies that evaluated the use of newer tests of VWF platelet binding activity (VWF:GPIbR, VWF:GPIbM) and VWF:RCo for the diagnosis of VWD (13 studies), VWF propeptide to VWF:Ag ratio, and desmopressin trial for the diagnosis of type 1C VWD (5 studies), VWF multimer analysis and VWF:CB/VWF:Ag ratio for the classification of type 2 VWD (11 studies), genetic testing and ristocetin-induced platelet aggregation to diagnose type 2B VWD (14 studies), genetic testing and FVIII:VWF binding to diagnose type 2N VWD (17 studies). Based on available diagnostic test accuracy, there appear to be comparable test accuracy results between newer tests of platelet binding activity of VWF function and VWF:RCo. The findings of these reviews support VWF multimer analysis or VWF:CB/VWF:Ag to diagnose type 2 VWD. The desmopressin trial test with 1- and 4-hour postinfusion blood work is the test of choice to confirm increased VWF clearance in patients with suspected VWD type 1C. Additionally, genetic testing is most useful in diagnosing type 2B VWD and has a role in the diagnostic algorithm of suspected type 2N VWD.

Physicians have difficulty recognizing and diagnosing disorders of primary hemostasis. The root of this may lie in their education, where students are often taught hemostasis using static graphics. We aimed to create a didactic animation on primary hemostasis for medical students to be used in North American medical schools. To promote widespread use of the animation, we surveyed hemostasis educators from Canada and the US on the animation’s learning objectives. The animation’s script and storyboard were developed using the Animation Processing Model (APM), a psychological processing model that addresses the perceptual limitations of learners. This animation is the first biomedical animation to use the APM in its design. Furthermore, this is the first didactic hemostasis animation which sought peer consensus for its learning objectives.

Introduction: von Willebrand disease (VWD) is an inherited bleeding disorder caused by a quantitative or qualitative dysfunction of von Willebrand factor. Clinicians, patients and other stakeholders have many questions about the diagnosis and management of the disease. Aim: To identify topics of highest importance to stakeholders that could be addressed by guidelines to be developed by the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF) and the World Federation of Hemophilia (WFH). Methods: A survey to determine and prioritize topics to be addressed in the collaborative development of guidelines for VWD was distributed to international stakeholders including patients, caregivers and healthcare providers (HCPs). Representatives of the four organizations coordinated the distribution strategy. The survey focused on both diagnosis and management of VWD, soliciting 7-point Likert-scale responses and open-ended comments, in English, French and Spanish. We conducted descriptive analysis with comparison of results by stakeholder type, gender and countries' income classification for the rating questions and qualitative conventional content data analysis for the open-ended responses. Results: A total of 601 participants responded to the survey (49% patients/caregivers and 51% healthcare providers). The highest priority topics identified were diagnostic criteria/classification, bleeding assessment tools and treatment options for women and surgical patients. In contrast, screening for anaemia and differentiating plasma-derived therapy versus recombinant therapies received lower ratings. Conclusion: This survey highlighted areas of importance to a diverse representation of stakeholders in the diagnosis and management of VWD, providing a framework for future guideline development and implementation.

Introduction From 2012 to 2014, a total of 17 family child care homes participated in a multisector, community-wide initiative to prevent obesity. Strategies included staff workshops, materials, site visits, and technical assistance regarding development and implementation of nutrition policies. The purpose of the evaluation was to examine the impact of the initiative on family child care home nutrition-related policies and practices and child dietary intake. Study design Pre- and post-intervention without control group. Measures taken at baseline and follow-up included structured observations and questionnaires regarding nutrition policies, practices, and environments; documentation of lunch foods served on 5 days; and lunch plate waste observations on 2 days. Paired t-tests were used to determine the significance of change over time. Setting/participants Seventeen family child care homes in a low-income diverse community in Northern California; children aged 2–5 years who attended the family child care homes. Main outcome measures Change in nutrition-related policies and practices, lunch foods served and consumed. Results Data was collected at 17 sites for an average of 5.2 children aged 2–5 years per site per day at baseline and 4.6 at follow-up for a total of 333 plate waste observations. There were significant increases in staff training, parental involvement, and several of the targeted nutrition-related practices; prevalence of most other practices either improved or was maintained over time. There were significant increases in the number of sites meeting Child and Adult Care Food Program meal guidelines, variety of fruit and frequency of vegetables offered, and reductions in frequency of juice and high-fat processed meats offered. Adequate portions of all food groups were consumed at both time points with no significant change over time. Conclusions A simple, policy-focused intervention by a child care resource and referral agency was successful at reinforcing and improving upon nutrition-related practices at family child care homes. Children consumed adequate, but not excessive, portions of the balanced meals served to them, suggesting there is no reason to offer unhealthy options. Supplement information This article is part of a supplement entitled Building Thriving Communities Through Comprehensive Community Health Initiatives, which is sponsored by Kaiser Permanente, Community Health.

How do you encourage students to engage effectively with classical Greek and Roman drama and its reception in the modern world in an online distance learning setting? That was the challenge facing the authors of this article while they collaborated on a section of a new Open University Masters’ course devoted to classical reception. The guiding pedagogical principle that underpins our study material is a multi-vocal approach that foregrounds the wealth of different perspectives, theories and methodologies inherent in the study of classical reception. Choosing performance reception as a paradigm for the whole field, we sought to bridge the gap between unseen lecturers and distance learners, creating a dynamic virtual classroom and equipping students with the skills to carry out further research in this thriving field of classical studies.

The objective of this scoping review is to summarize the current use of pharmacokinetics for tailoring prophylaxis in hemophilia patients switching between clotting factor products. Patients with hemophilia may require switching of clotting factor concentrates due to a variety of factors, but there have been perceived risks associated with switching, such as inhibitor development or suboptimal protection due to inadequate dosing while titrating treatment. Studies that look at patients switching from one clotting factor concentrate to another are categorized in terms of their primary and/or secondary objectives, notably biosimilarity and comparative pharmacokinetic studies and inhibitor development studies. Research on how best to switch concentrates with respect to dosing regimen are lacking, and currently a trial-and-error approach is used for dosing the new factor concentrate. In the future, studies looking at the predictability of pharmacokinetics (PK) of a new factor concentrate based on individual PK knowledge of the original factor concentrate may offer clinical benefit by providing a safer switching approach and protocol.

Introduction Reaching preschool-aged children to establish healthy lifestyle habits, including physical activity, is an important component of obesity prevention efforts. However, few studies have examined family child care homes where nearly 1 million children receive care. Study design A pre- and post-intervention evaluation without a control group was conducted to evaluate what changes occurred in family child care homes that participated in the Healthy Eating and Active Living project, a multicomponent obesity prevention initiative, focused on community-driven policy and environmental change in neighborhoods within Kaiser Permanente service areas. Setting/participants From 2012 to 2014, a total of 17 family child care homes in Northern California participated in the intervention. Intervention A physical activity workshop for child care staff and technical assistance to develop a policy to promote physical activity and other healthy behaviors. Main outcome measures Pre and post observations, questionnaires, and physical activity logs were completed to assess change in physical activity resources available in the family child care homes, the amount of child screen time offered, type and amount of physical activity offered to children, and implementation of physical activity best practices. Results Between baseline and follow-up, providers significantly increased both the number of structured, adult-led activities (2.6 vs 3.2 activities per day) and the number of structured, adult-led minutes of activity in which children participated (49 vs 83 minutes per day). Providers also improved screen time practices and made improvements to the physical activity environment. Conclusions In this study, a community-based organization designed and implemented multicomponent strategies tailored for participating family child care homes. The successful implementation of the intervention likely contributed to implementation of practices that increased opportunities for physical activity for the young children attending these family child care homes. Supplement information This article is part of a supplement entitled Building Thriving Communities Through Comprehensive Community Health Initiatives, which is sponsored by Kaiser Permanente, Community Health.

Guidelines state that Ringer’s lactate (RL) should not be co-administered with packed red blood cells (PRBC) due to a potential risk of clotting. The purpose of this study was to determine whether RL causes clotting in PRBC with the currently used preservative, saline-adenine-glucose-mannitol (SAGM). Phase 1: Samples from 12 units of SAGM-PRBC were diluted from 0-97.5% with RL and normal saline (NS), incubated for 30 min, and passed through 40 μm filters. Additional samples were frozen and batch analyzed using an enzyme-linked immunosorbent assay (ELISA) to measure prothrombin activation fragment 1 + 2 (F1 + 2), indicative of thrombin generation. Packed red blood cells were also diluted, flushed with crystalloid using a rapid transfusion model, and filtered. Phase 2: Eight further units were serially diluted with RL and incubated for 30, 60, 120, 180, and 240 min. Fresh samples were analyzed by filtration and ELISA. Phase 1: No clotting was seen during filtration or using the transfusion model with NS or RL. The F1 + 2 ranged from 2.28 to 154.37 pmol·L−1 in NS dilutions and from 2.80 to 1675.93 pmol·L−1 in RL dilutions, indicating coagulation in some samples. Phase 2: No clotting was observed within 60 min by filtration or ELISA. However, 4 of the 8 units showed clots in the filters of some dilutions between 120 and 240 min. No clotting was detected at any dilution of RL with SAGM- preserved PRBC within 60 min, but clotting was detected with extended incubation. The results indicate RL can be safely co-administered with PRBC during rapid transfusion (

In this article I suggest ways in which a gorgeously crafted, colourful, compelling 20th century painting of an abandoned Ariadne highlights both her tragic and comic presence in classical literary representations. Joseph Southall's 1925-6 work Ariadne in Naxos (tempera on linen, 83.5 x 101.6 cm), can be viewed in all its glory in the Birmingham City Art Gallery (bequeathed by the artist's widow, Anne Elizabeth, in 1948) but it was featured to fine effect in the 2007 exhibition The Parrot in Art: From D rer to Elizabeth Butterworth, Barber Institute of Fine Arts, University of Birmingham. It was in this psittacine (psittaceous?) context that I first encountered Ariadne's parrot so the bird perhaps loomed larger in the painting than it might as a stand-alone Southall on its home ground in the Gallery. The very presence of the parrot in this painting suggests a symbolic array to those familiar with Ariadne's mythical traditions and simultaneously attuned to the possibilities of the parrot as a trickster in both visual and written texts. Southall's painting with its foregrounding of the parrot functions as a mnemonic for Ariadne's portrayal in the poetry of Catullus and Ovid. For this reason, Southall's painting would provide stimulating seminar material, being both a visual feast and a discussion point for Ariadne's literary registers.

Purpose. To test whether implementing a staff wellness program affects the nutrition and physical activity environment at child care centers. Design. Quasi-experimental controlled trial. Setting. Child care centers in low income neighborhoods in California. Subjects. Eighty-two staff members at 13 centers completed the study. Intervention. Intervention and control groups received training and education about nutrition and physical activity. The intervention group also participated in a worksite wellness program. Measures. Staff members' personal health habits, self-efficacy in working with families on nutrition and physical activity, and changes in children's food and physical activity environments were assessed. Analysis. Statistical software was used to analyze change scores for pre-post measures and to test differences for end point—only measures. Results. Although significant differences in staff members' personal health behaviors were not observed, staff from intervention sites exhibited more positive changes in their comfort level in talking to parents about nutrition and physical activity. Intervention sites reported providing more fresh fruits (p = .004) and vegetables (p = .03) to children as part of regular meals and snacks and serving more fresh fruits (p = .05) at children's celebrations. Control sites reported greater increases in sweetened foods (p = .02) and sweetened beverages (p = .05) at children's celebrations. Conclusion. The wellness intervention shows promise in improving the children's food environment in a child care setting.