The impact of exercise-induced core body temperature elevations on coagulation responses.

OBJECTIVES: Exercise induces changes in haemostatic parameters and core body temperature (CBT). We aimed to assess whether exercise-induced elevations in CBT induce pro-thrombotic changes in a dose-dependent manner. DESIGN: Observational study. METHODS: CBT and haemostatic responses were measured in 62 participants of a 15-km road race at baseline and immediately after finishing. As haemostasis assays are routinely performed at 37°C, we corrected the assay temperature for the individual's actual CBT at baseline and finish in a subgroup of n=25. RESULTS: All subjects (44±11 years, 69% male) completed the race at a speed of 12.1±1.8km/h. CBT increased significantly from 37.6±0.4°C to 39.4±0.8°C (p<0.001). Post-exercise, haemostatic activity was increased, as expressed by accelerated thrombin generation and an attenuated plasmin response. Synchronizing assay temperature to the subjects' actual CBT resulted in additional differences and stronger acceleration of thrombin generation parameters. CONCLUSIONS: This study demonstrates that exercise induces a prothrombotic state, which might be partially dependent on the magnitude of the exercise-induced CBT rise. Synchronizing the assay temperature to approximate the subject's CBT is essential to obtain more accurate insight in the haemostatic balance during thermoregulatory challenging situations. Finally, this study shows that short-lasting exposure to a CBT of 41.2°C does not result in clinical symptoms of severe coagulation. We therefore hypothesize that prolonged exposure to a high CBT or an individual-specific CBT threshold needs to be exceeded before derailment of the haemostatic balance occurs

The transition of Dutch social housing corporations to sustainable business models for new buildings and retrofits

Social housing corporations play an important role in society as they provide affordable and good-quality housing for vulnerable citizens. Yet, the sector has to deal with the historical legacy of a high number of old and poorly insulated buildings. While research into the processes that drive or hinder business model innovation in this sector is scarce, this paper draws upon multiple qualitative case studies of social housing in the Netherlands to identify critical success factors for the transition to sustainable business models for new buildings and retrofits. Results show that there are four key attributes for a successful transition process: collaboration (both with supply chain partners as well as other social housing associations); continuous innovation; vision; and the role of the government (including subsidies and fiscal regulations). While economic performance was an important boundary condition, sustainability was not always seen as a strategic organizational objective, a finding that might be explained through considering the legacy of social housing corporations. Furthermore, a number of barriers were identified including the need for customer acceptance, a lack of support from the construction sector and government and macroeconomic factors such as increased construction costs

EXPRESS: Learning from Data: An Empirics-First Approach to Relevant Knowledge Generation

A “theory-first” paradigm tends to be the dominant approach in much academic marketing research. In this approach, a theory is borrowed, refined, or developed and then tested empirically. In this challenging-the-boundaries article, we make a case for an “empirics-first” approach. Empirics-first refers to research that (i) is grounded in (originates from) a real-world marketing phenomenon, problem, or observation, (ii) involves obtaining and analyzing data, and (iii) produces valid marketing-relevant insights without necessarily developing or testing theory. The empirics-first approach is not antagonistic to theory but rather can serve as a stepping-stone to theory. The approach lends itself well to today’s data-rich environment, which can surface novel research questions untethered to theory. The present paper describes the underlying principles of an empirics-first approach, which consists of exploring a domain purposefully without preconceptions. Using a rich set of published examples, the present paper offers guidance on how to implement empirics-first research and how it can lead to valuable knowledge development. Advice is also offered to authors on how to report EF research and to reviewers and to editorial teams on how to evaluate it. Our ultimate objective is to pave a way for empirics-first to enter the mainstream of academic marketing research

High prevalence of heavy menstrual bleeding in women with rare bleeding disorders in the Netherlands:retrospective data from the RBiN study

Background: Heavy menstrual bleeding (HMB) is associated with a reduced quality of life and limitations in social and physical functioning. Data on HMB in women with rare bleeding disorders (RBDs), including coagulation factor deficiencies and fibrinolytic disorders, are scarce. Objectives: To analyze the prevalence, severity, and treatment of HMB in Dutch women with an RBD. Methods:The Rare Bleeding Disorders in the Netherlands (RBiN) study included 263 patients with an RBD from all 6 hemophilia treatment centers (October 2017-November 2019). In this analysis, data of 111 women aged ≥16 years were studied. According to the International Society on Thrombosis and Haemostasis bleeding assessment tool, HMB symptoms were scored from 0 (no/trivial) to 4 (severe symptoms requiring medical intervention). HMB was defined as a score ≥1. Age at RBD diagnosis was extracted from patient files. Results: HMB was reported by 80% of women (89/111) and was more prevalent in women with a fibrinolytic disorder (33/35; 94%) than in women with a coagulation factor deficiency (56/76; 74%) (P = .011). Of the 89 women with HMB, 82% (n = 73) ever required treatment. Multiple treatment modalities were frequently used, both in severe and mild deficiencies. Hormonal treatment was mostly used (n = 64; 88%), while antifibrinolytics were prescribed less frequently (n = 18; 25%). In women with HMB since menarche (n = 61; 69%), median age at RBD diagnosis was 28 years (IQR, 14-41).Conclusion: HMB is common in women with RBDs. Women with mild deficiencies also frequently reported HMB. Only a minority of women were treated with hemostatic agents. A significant diagnostic delay was observed after the onset of HMB symptoms.</p

Importance of Genotyping in von Willebrand Disease to Elucidate Pathogenic Mechanisms and Variability in Phenotype

Genotyping is not routinely performed at diagnosis of von Willebrand disease (VWD). Therefore, the association between genetic variants and pathogenic mechanism or the clinical and laboratory phenotype is unknown in most patients, especially in type 1 VWD. To investigate whether genotyping adds to a better understanding of the pathogenic mechanisms and variability in phenotype, we analyzed the VWF gene in 390 well-defined VWD patients, included in the WiN study. A VWF gene variant was found in 155 patients (61.5%) with type 1, 122 patients (98.4%) with type 2, and 14 patients (100%) with type 3 VWD. Forty-eight variants were novel. For each VWF gene variant, the pathogenic mechanisms associated with reduced VWF levels was investigated using the FVIII:C/VWF:Ag and VWFpp/VWF:Ag ratios. In type 1 VWD, reduced synthesis or secretion of VWF was most frequently found in patients with nonsense variants, frameshift variants, and deletions, whereas rapid clearance of VWF was mainly found in patients with missense variants. Furthermore, type 1 VWD patients with and without a VWF gene variant were clearly distinct in their clinical features such as age of diagnosis, laboratory phenotype, and bleeding phenotype. In type 2 VWD, 81% of variants were associated with an increased clearance of VWF. To conclude, we identified the pathogenic mechanisms associated with various VWF gene variants in type 1, 2, and 3 VWD patients. Additionally, major differences in the phenotype of type 1 VWD patients with and without a variant were observed, which may be of importance for clinical management

Major differences in clinical presentation, diagnosis and management of men and women with autosomal inherited bleeding disorders

Background: In recent years, more awareness is raised about sex-specific dilemmas in inherited bleeding disorders. However, no large studies have been performed to assess differences in diagnosis, bleeding phenotype and management of men and women with bleeding disorders. Therefore, we investigated sex differences in a large cohort of well-defined patients with autosomal inherited bleeding disorders (von Willebrand disease (VWD), rare bleeding disorders (RBDs) and congenital platelet defects (CPDs)).Methods: We included patients from three nationwide cross-sectional studies on VWD, RBDs and CPDs in the Netherlands, respectively the WiN, RBiN and TiN study. In all studies a bleeding score (BS) was obtained, and patients filled in an extensive questionnaire on the management and burden of their disorder.Findings: We included 1092 patients (834 VWD; 196 RBD; 62 CPD), of whom 665 (60.9%) were women. Women were more often referred because of a bleeding diathesis than men (47.9% vs 36.6%, p = 0.002). Age of first bleeding was similar between men and women, respectively 8.9 +/- 13.6 (mean +/- sd) years and 10.6 +/- 11.3 years (p = 0.075). However, the diagnostic delay, which was defined as time from first bleeding to diagnosis, was longer in women (11.6 +/- 16.4 years) than men (7.7 +/- 16.6 years, p = 0.002). Similar results were found when patients referred for bleeding were analyzed separately. Of women aging 12 years or older, 469 (77.1%) had received treatment because of sex-specific bleeding.Interpretation: Women with autosomal inherited bleeding disorders are more often referred for bleeding, have a longer diagnostic delay, and often require treatment because of sex-specific bleeding. (C) 2021 The Authors. Published by Elsevier Ltd.Clinical epidemiolog

Construction and psychometric testing of the EMPATHIC questionnaire measuring parent satisfaction in the pediatric intensive care unit

Abstract PURPOSE: To construct and test the reliability and validity of the EMpowerment of PArents in THe Intensive Care (EMPATHIC) questionnaire measuring parent satisfaction in the pediatric intensive care unit (PICU). METHODS: Structured development and psychometric testing of a parent satisfaction-with-care instrument with the results of two cohorts of parents (n = 2,046) from eight PICUs in the Netherlands. RESULTS: In the first cohort, 667/1,055 (63%) parents participated followed by 551/991 (56%) parents in the second cohort. The empirical structure of the instrument was established by confirmatory factor analysis with the first sample of parents confirming 65 statements within five theoretically conceptualized domains: information, care and cure, organization, parental participation, and professional attitude. The standardized factor loadings were greater than 0.40 in 63 statements. Cronbach's α, a measure of reliability, per domain ranged from 0.73 to 0.93 in both cohorts with no significant difference documenting the reliability over time. Beside rigorous content and face validity, the congruent validity of the instrument showed adequate correlation with four gold standard questions measuring overall satisfaction. The non-differential validity was confirmed with no significant differences between the population characteristics and the domains, except that parents with a child for a surgical admission were more satisfied on information issues. CONCLUSIONS: The final EMPATHIC questionnaire incorporates 65 statements. The empirical structure of the satisfaction statements and domains was satisfactory. The reliability and validity proved to be adequate. The EMPATHIC questionnaire is a valid quality performance indicator to measure quality of care as perceived by parents

The spectrum of neutralizing and non-neutralizing anti-FVIII antibodies in a nationwide cohort of 788 persons with hemophilia A

ObjectivesAnti-factor VIII (FVIII) antibodies have been reported to exhibit both neutralizing and non-neutralizing characteristics. This is the first study investigating the full spectrum of FVIII-specific antibodies, including non-neutralizing antibodies, very-low titer inhibitors, and inhibitors, in a large nationwide population of persons with hemophilia A of all severities.MethodsAll persons with hemophilia A (mild (FVIII &gt; 5–40 IU/dL)/moderate [FVIII 1–5 IU/dL)/severe (FVIII &lt; 1 IU/dL)] with an available plasma sample who participated in the sixth Hemophilia in the Netherlands study between 2018 and 2019 were included. The presence of anti-FVIII antibodies of the immunoglobulin A, M, and G isotypes and IgG subclasses, along with antibody titer levels, were assessed using direct-binding ELISAs. FVIII specificity was assessed using a competition-based ELISA approach. The inhibitor status was determined using the Nijmegen ultra-sensitive Bethesda assay (NusBA) and the Nijmegen Bethesda assay (NBA).ResultsIn total, 788 persons with hemophilia A (336 (42.6%) mild, 123 (15.6%) moderate, 329 (41.8%) severe hemophilia) were included. The median age was 45 years (IQR 24–60), and the majority (50.9%) had over 150 exposure days to FVIII concentrates. Within our population, 144 (18.3%) individuals had non-neutralizing FVIII-specific antibodies, 10 (1.3%) had very low-titer inhibitors (NusBA positive; NBA negative), and 13 (1.6%) had inhibitors (both NusBA and NBA positive). IgG1 was the most abundant FVIII-specific antibody subclass, and the highest titer levels were found for IgG4. In individuals without a reported history of inhibitor development, no clear differences were observed in antibody patterns between those who were minimally or highly exposed to FVIII concentrates. IgG4 subclass antibodies were only observed in persons with a reported history of FVIII inhibitor or in those with a currently detected (very low-titer) inhibitor.ConclusionIn this cross-sectional study, we identified non-neutralizing antibodies in a relatively large proportion of persons with hemophilia A. In contrast, in our population, consisting of persons highly exposed to FVIII concentrates, (very low-titer) inhibitors were detected only in a small proportion of persons, reflecting a well-tolerized population. Hence, our findings suggest that only a small subpopulation of non-neutralizing FVIII-specific antibodies is associated with clinically relevant inhibitors