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Background Atresia of the infrarenal inferior vena cava (IVC) is associated with thrombophilia and antithrombin (AT) deficiency (ATD) due to homozygosity for the so-called Budapest 3 variant, c.391C > T, in the gene, SERPINC1 . Case presentation We report on a father and his two sons that had severe thrombosis at a young age. One son had absence of, and the other had very gracile infrarenal IVC. The father had gracile vena iliaca. All had significant collateral building. AT activity was determined with four different methods and varied between moderately reduced and borderline normal values, depending on the method. While all were heterozygous for c.391C > T, the father was also heterozygous for a variant of uncertain significance in SERPINC1 . Conclusions The findings support the association between c.391C > T in SERPINC1 , thrombophilia, and atresia of the IVC system and indicate that even heterozygosity for c.391C > T may contribute to such anomalies. ATD detection was hampered by the varying sensitivity of methods used for AT activity measurement.

Background Clinical practice is essential for health care students. The supervisor’s role and how supervision should be organized are challenging issues for educators and clinicians. Clinical education wards have been established to meet these challenges and they are units with a pedagogical framework facilitating students’ training in real clinical settings. Supervisors support students to link together theoretical and practical knowledge and skills. From students’ perspectives, clinical education wards have shown potential to enhance students’ learning. Thus there is a need for deeper understanding of supervisors’ pedagogical role in this context. We explored supervisors’ approaches to students’ learning at a clinical education ward where students are encouraged to independently take care of patients. Method An ethnographic approach was used to study encounters between patients, students and supervisors. The setting was a clinical education ward for nursing students at a university hospital. Ten observations with ten patients, 11 students and five supervisors were included in the study. After each observation, individual follow-up interviews with all participants and a group interview with supervisors were conducted. Data were analysed using an ethnographic approach. Results Supervisors’ pedagogical role has to do with balancing patient care and student learning. The students were given independence, which created pedagogical challenges for the supervisors. They handled these challenges by collaborating as a supervisory team and taking different acts of supervision such as allowing students their independence, being there for students and by applying patient-centredness. Conclusion The supervisors’ pedagogical role was perceived as to facilitate students’ learning as a team. Supervisors were both patient- and student-centred by making a nursing care plan for the patients and a learning plan for the students. The plans were guided by clinical and pedagogical guidelines, individually adjusted and followed up.

Background/Objectives: Cancer progression and the hemostatic system are closely linked. Coagulation factor V (FV) has a key function in coagulation, with both pro- and anticoagulant functions. FV gene (F5) expression and F5 variants have been linked to breast cancer progression. The direct impact of F5 variants on FV expression and functional effects in breast cancer are unknown. We aimed to investigate whether the F5 variants FV Leiden (F5 rs6025) and F5 rs6028 influenced FV expression, coagulant activity, and apoptosis in breast cancer cells. Methods: MDA-MB-231 cells were transfected with overexpression plasmids containing F5 wild type, F5 rs6025 or F5 rs6028. We investigated the functional impact of the F5 variants on F5 mRNA, FV protein, FV coagulant activity, and apoptosis in vitro, and examined the potential of the variants as transcriptional regulators of F5 expression in silico. Results: Increased F5 mRNA, FV protein, and apoptosis were observed in cells transfected with F5 wild-type overexpression plasmid compared to empty vector. F5 mRNA, protein, coagulant activity, and apoptosis were further increased with the F5 rs6025 and F5 rs6028 variants compared to F5 wild type. Cis-expression quantitative trait loci analyses indicated a regulatory effect of F5 rs6028, and putative transcription factor binding sites for several transcription factors overlapped with the position of F5 rs6025. Conclusions: Our study demonstrated that F5 rs6025 and F5 rs6028 have a regulatory effect on FV synthesis that might affect apoptosis in breast cancer. The F5 variants might therefore enhance the tumor suppressor function of FV in breast cancer.

Background The aim of the study was to investigate how the expression of adhesion molecules changes as neutrophils migrate from the circulation to the lung and if these changes differ between non-smoking subjects and smokers with and without COPD. Methods Non-smoking healthy subjects (n=22), smokers without (n=21) and with COPD (n=18) were included. Neutrophils from peripheral blood, sputum and bronchial biopsies were analysed for cell surface expression of adhesion molecules (CD11b, CD62L, CD162). Serum, sputum supernatant and BAL-fluid were analysed for soluble adhesion molecules (ICAM-1, -3, E-selectin, P-selectin, VCAM-1, PECAM-1). Results Expression of CD11b was increased on circulating neutrophils from smokers with COPD. It was also increased on sputum neutrophils in both smokers groups, but not in non-smokers, as compared to circulating neutrophils. Serum ICAM-1 was higher in the COPD group compared to the other two groups (p<0.05) and PECAM-1 was lower in smokers without COPD than in non-smoking controls and the COPD group (p<0.05). In BAL-fluid ICAM-1 was lower in the COPD group than in the other groups (p<0.05). Conclusions Thus, our data strongly support the involvement of a systemic component in COPD and demonstrate that in smokers neutrophils are activated to a greater extent at the point of transition from the circulation into the lungs than in non-smokers.

Living with rheumatoid arthritis (RA) poses physiological and psychological demands on a person. RA is a autoimmune disease that can cause pain, disability, and suffering. The ability to notice bodily inner sensations and stimuli (body awareness, BA) is described in the literature in ways that could have either a positive or a negative impact on a person's health. The concept of BA is complex and a thorough understanding is needed about what BA means from the patient's perspective. This study was therefore conducted to acquire greater insight into this phenomenon. The study is grounded in a phenomenological life-world perspective. Eighteen narrative interviews were conducted in patients (age range 23-78 years) with RA. The interviews were analyzed using the Empirical Phenomenological Psychological method. General characteristics were found running through all 18 interviews, indicating that the disease resulted in a higher degree of negatively toned BA. BA was either a reactive process of searching or controlling after disease-related symptoms or a reactive process triggered by emotions. BA was an active process of taking an inventory of abilities. All participants had the ability to shift focus from BA to the outside world. Four typologies were identified: \"A reactive process on symptoms,\" \"A reactive process on emotional triggers,\" \"An active process of taking an inventory of abilities,\" and \"A shifting from BA to the outside world.\" In conclusion, because BA can be both positively and negatively toned, health care professionals must have a good understanding of when BA is positive and when it is negative in relation to the patient. RA had caused a higher degree of negatively toned BA. Thus, the ability to shift attention from BA to activity in the outside world could sometimes be beneficial for the patient's general health.

Background An increasing number of patients are treated with direct-acting oral anticoagulants (DOACs), but the optimal way to reverse the anticoagulant effect is not known. Specific antidotes are not available and prothrombin complex concentrate (PCC), activated PCC (aPCC) and recombinant factor VIIa (rFVIIa) are variously used as reversal agents in case of a major bleeding. We aimed to determine the most effective haemostatic agent and dose to reverse the effect of rivaroxaban in blood samples from patients taking rivaroxaban for therapeutic reasons. Methods Blood samples from rivaroxaban-treated patients ( n =  50) were spiked with PCC, aPCC and rFVIIa at concentrations imitating 80%, 100% and 125% of suggested therapeutic doses. The reversal effect was assessed by thromboelastometry in whole blood and a thrombin generation assay (TGA) in platelet-poor plasma. Samples from healthy subjects ( n =  40) were included as controls. Results In thromboelastometry measurements, aPCC and rFVIIa had a superior effect to PCC in reversing the rivaroxaban-induced lenghtening of clotting time (CT). aPCC was the only haemostatic agent that shortened the CT down to below the control level. Compared to healthy controls, patients on rivaroxaban also had a prolonged lag time and decreased peak concentration, velocity index and endogenous thrombin potential (ETP) in platelet-poor plasma. aPCC reversed these parameters more effectively than rFVIIa and PCC. There were no differences in efficacy between 80%, 100% and 125% doses of aPCC. Conclusions aPCC seems to reverse the anticoagulant effect of rivaroxaban more effectively than rFVIIa and PCC by evaluation with thromboelastometry and TGA in vitro.

Levels of bacterial LPS, pro-inflammatory cytokines and IL-10 are related to the severity of meningococcal septicaemia. Patients infected with a Neisseria meninigitidis lpxL1 mutant (Nm-mutant) with penta-acylated lipid A present with a milder meningococcal disease than those infected with hexa-acylated Nm wild type (Nm-wt). The aim was to compare the pro-inflammatory responses after ex vivo incubation with the heat-inactivated Nm-wt or the Nm-mutant in citrated whole blood, and the modulating effects of IL-10. Concomitantly, we measured intracellular IL-6, IL-8 and TNF-α to elucidate which cell types were responsible for the pro-inflammatory responses. Incubation with Nm-wt (106/ml;107/ml;108/ml) resulted in a dose-dependent increase of the MyD88-dependent pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α), which were mainly derived from monocytes. In comparison, only 108/ml of the Nm-mutant significantly increased the concentration of these cytokines. The MyD88-independent cytokines (IP-10, RANTES) were evidently increased after incubation with the Nm-wt but were unaffected by the Nm-mutant. Co-incubation with IL-10 significantly reduced the concentrations of the MyD88-dependent cytokines induced by both the Nm-wt and the Nm-mutant, whereas the MyD88-independent cytokines were almost unaffected. In summary, the Nm-mutant is a weaker inducer of the MyD88-dependent/independent cytokines than the Nm-wt in whole blood, and IL-10 attenuates the Nm-stimulated increase in MyD88-dependent pro-inflammatory cytokines.

Fibroblast growth factor 21 (FGF21) analogs have significant therapeutic potential in metabolic dysfunction–associated steatohepatitis (MASH) but limited body weight effects in patients with MASH. This study investigated the effect of combined treatment with the FGF21 analog zalfermin and the glucagon-like peptide-1 receptor agonist semaglutide on body weight and plasma and liver biochemistry and histology in a mouse model of MASH. Amylin liver nonalcoholic steatohepatitis diet-induced obese-MASH mice with biopsy-confirmed MASH and fibrosis were administered (subcutaneous [SC], daily [QD]) vehicle, zalfermin (0.05 or 0.2 mg/kg), semaglutide (3 or 120 µg/kg), or zalfermin 0.05 mg/kg + semaglutide 3 µg/kg for 8 weeks (n = 11–12 per group). Vehicle-dosed (SC, QD) chow-fed mice served as normal controls (n = 10). Pre- to post-liver biopsy histology was compared for within-subject evaluation of changes in non-alcoholic fatty liver disease Activity Score (NAS), fibrosis stage, and quantitative histology. Additional endpoints included plasma/liver biochemistry and liver RNA sequencing. Combined low-dose zalfermin and semaglutide treatment resulted in super-additive body weight loss (−18%) vs. individual low-dose monotherapies (zalfermin, −6%; semaglutide, −4%) and was equally effective as high-dose zalfermin monotherapy (−16%) and semaglutide (−15%). Low-dose combination therapy promoted greater benefits on transaminases, total cholesterol and triglycerides, NAS, steatosis, and inflammation vs. individual low-dose monotherapies and high-dose semaglutide, and high-dose zalfermin was as effective as the low-dose combination therapy on most endpoints. Combination treatment reduced gene expression markers of fibrosis to a greater degree than monotherapies. In conclusion, combined low-dose zalfermin and semaglutide, as well as high-dose zalfermin, resulted in beneficial effects on body weight and biochemical and histological endpoints, supporting the clinical development of zalfermin as therapy for patients with MASH.

Background Critiques of cost-effectiveness modelling in type 1 diabetes mellitus (T1DM) are scarce and are often undertaken in combination with type 2 diabetes mellitus (T2DM) models. However, T1DM is a separate disease, and it is therefore important to appraise modelling methods in T1DM. Objectives This review identified published economic models in T1DM and provided an overview of the characteristics and capabilities of available models, thus enabling a discussion of best-practice modelling approaches in T1DM. Methods A systematic review of Embase ® , MEDLINE ® , MEDLINE ® In-Process, and NHS EED was conducted to identify available models in T1DM. Key conferences and health technology assessment (HTA) websites were also reviewed. The characteristics of each model (e.g. model structure, simulation method, handling of uncertainty, incorporation of treatment effect, data for risk equations, and validation procedures, based on information in the primary publication) were extracted, with a focus on model capabilities. Results We identified 13 unique models. Overall, the included studies varied greatly in scope as well as in the quality and quantity of information reported, but six of the models (Archimedes, CDM [Core Diabetes Model], CRC DES [Cardiff Research Consortium Discrete Event Simulation], DCCT [Diabetes Control and Complications Trial], Sheffield, and EAGLE [Economic Assessment of Glycaemic control and Long-term Effects of diabetes]) were the most rigorous and thoroughly reported. Most models were Markov based, and cohort and microsimulation methods were equally common. All of the more comprehensive models employed microsimulation methods. Model structure varied widely, with the more holistic models providing a comprehensive approach to microvascular and macrovascular events, as well as including adverse events. The majority of studies reported a lifetime horizon, used a payer perspective, and had the capability for sensitivity analysis. Conclusions Several models have been developed that provide useful insight into T1DM modelling. Based on a review of the models identified in this study, we identified a set of ‘best in class’ methods for the different technical aspects of T1DM modelling.