Patients with metabolic dysfunction-associated steatotic liver disease have preserved in vitro responses to antiplatelet drugs.

Background: Patients with metabolic dysfunction-associated steatotic liver disease (MASLD) are at a risk of developing cardiovascular disease. Antiplatelet therapy not only prevents cardiovascular disease in these patients, but may also lower the risk of progression into advanced stages of fibrosis. However, patients with MASLD-associated cirrhosis often have complex changes in the hemostatic system and have been excluded from randomized trials. Objectives: The aim of this study was to assess the potency of antiplatelet drugs in these patients with MASLD-associated cirrhosis. Methods: We included patients with MASLD-associated cirrhosis (n = 19), patients with type 2 diabetes (DM2) and steatosis (n = 22), patients with steatosis only (n = 15), and healthy controls (n = 20). We measured basal platelet aggregation and activation using light transmission aggregometry and flow cytometry. We subsequently measured platelet aggregation and activation after in vitro addition of aspirin, cangrelor, and ticagrelor and compared the antiplatelet response in patients and healthy controls. Results: Rates of aspirin resistance as measured by light transmission aggregometry were similar between patients with MASLD-associated cirrhosis and healthy controls (21% vs 16%), but were significantly higher in patients with DM2 and steatosis (50% [P = .02] vs controls) and patients with steatosis only (53% [P = .05] vs controls). In patients with DM2 and steatosis, but not with MASLD-associated cirrhosis, the potency of cangrelor was significantly lower than that in healthy controls (P = .028). Conclusion: The in vitro potency of aspirin, cangrelor, and ticagrelor in samples of patients with MASLD-associated cirrhosis is similar to that of healthy controls. In contrast, the potency of commonly used antiplatelet drugs may be altered in patients with DM2 and steatosis and in patients with steatosis only.

[A diabetic patient with a fulminant hand infection caused by a domestic rat bite]. / Ernstige handinfectie bij een patiënt met diabetes door een tamme-rattenbeet.

BACKGROUND: Animal bite wounds are common and can cause serious hand infections. Risk factors not only include the oral flora of the animal and the anatomy of the teeth, but also the comorbidities of the bitten patient. CASE DESCRIPTION: In this case report we describe a 46-years old female patient with comorbidities, including diabetes mellitus type 2 and peripheral artery disease, suffering a fulminant hand infection after a domestic rat bite with the newly described bacterium Rodentibacterratti. Despite extensive antibiotic therapy and surgical debridement, a ray amputation was inevitable to maintain adequate hand function. CONCLUSION: Infections after animal bites may be caused by a variety of pathogens. The pathogen Rodentibacterratti has not previously been associated with infections in humans and future research is indicated to assess therapeutic strategies. Patients should be referred to a (plastic) surgeon if there is no clinical improvement within 48 hours of initiating antibiotic treatment.

Von Willebrand factor is an independent predictor of short-term mortality in acutely ill patients with cirrhosis.

BACKGROUND AND AIMS: Levels of von Willebrand factor (VWF) are elevated in patients with cirrhosis, and correlate well with disease severity. In patients with decompensated cirrhosis (DC), plasma VWF is associated with mortality. The value of VWF in predicting short-term mortality risk in patients with acute-on-chronic liver failure (ACLF) is, however, unclear. METHODS: We included patients with DC (n = 111) and ACLF (n = 105). We measured VWF levels and correlated these with other laboratory parameters and prediction models for mortality. Also, we assessed the predictive value of VWF in the prediction of 90- and 30-day mortality in patients with DC and ACLF, respectively, and compared this to the predictive value of clinically used prediction models. Finally, we determined the optimal cut-off value for VWF in patients with ACLF. RESULTS: Sixteen of 111 (14%) patients with DC and 35 of 105 (33%) with ACLF died within 90 and 30 days, respectively. VWF was associated with mortality and correlated closely with other prediction models. In patients with ACLF, VWF levels had a discrimination for 30-day mortality comparable with these models and accurately identified ACLF patients with high 30-day mortality risk. CONCLUSIONS: Levels of VWF associate closely with risk of mortality in patients with DC and ACLF, and may have predictive utility as a laboratory marker of prognosis. Further research is warranted to assess the additional value of VWF in the prediction of mortality and associated complications in chronic liver failure syndromes.

The international normalised ratio to monitor coagulation factor production during normothermic machine perfusion of human donor livers.

BACKGROUND: Normothermic machine perfusion (NMP) of donor livers allows for new diagnostic and therapeutic strategies. As the liver produces most of the haemostatic proteins, coagulation assays such as the International Normalised Ratio (INR) performed in perfusate may be useful to assess hepatocellular function of donor livers undergoing NMP. However, high concentrations of heparin and low levels of fibrinogen may affect coagulation assays. METHODS: Thirty donor livers that underwent NMP were retrospectively included in this study, of which 18 were subsequently transplanted. We measured INRs in perfusate in presence or absence of exogenously added fibrinogen and/or polybrene. Additionally, we prospectively included 14 donor livers that underwent NMP (of which 11 were transplanted) and measured INR using both a laboratory coagulation analyser and a point-of-care device. RESULTS: In untreated perfusate samples, the INR was above the detection limit in all donor livers. Addition of both fibrinogen and polybrene was required for adequate INR assessment. INRs decreased over time and detectable perfusate INR values were found in 17/18 donor livers at the end of NMP. INR results were similar between the coagulation analyser and the point-of-care device, but did not correlate with established hepatocellular viability criteria. CONCLUSIONS: Most of the donor livers that were transplanted showed a detectable perfusate INR at the end of NMP, but samples require processing to allow for INR measurements using laboratory coagulation analysers. Point-of-care devices bypass this need for processing. The INR does not correlate with established viability criteria and might therefore have additional predictive value.

Pathophysiology and management of bleeding and thrombosis in patients with liver disease.

Patients with liver disease often develop complex changes in their haemostatic system. Frequently observed changes include thrombocytopaenia and altered plasma levels of most of the proteins involved in haemostasis. Although liver disease was historically classified as a haemostasis-related bleeding disorder, it has now been well established that the antihaemostatic changes that promote bleeding are compensated for by prohaemostatic changes. Conventional coagulation tests however do not accurately reflect these prohaemostatic changes, resulting in an underestimation of haemostatic potential. Novel coagulation tests, such as viscoelastic tests (VETs) and thrombin generation assays (TGAs) better reflect the net result of the haemostatic changes in patients with liver disease, and demonstrate a new, "rebalanced" haemostatic status. Although rebalanced, this haemostatic status is more fragile than in patients without liver disease. Patients with liver disease are therefore not only at risk of bleeding but also at risk of thrombosis. Notably, however, many haemostatic complications in liver disease are not related to the haemostatic failure. It is, therefore, crucial to identify the cause of the bleed or thrombotic complication in order to provide adequate treatment. In this paper, we will elaborate on the haemostatic changes that occur in liver disease, reflect on laboratory and clinical studies over the last few years, and explore the pathophysiologies of bleeding and thrombosis in this specific patient group.

Heparins have adequate ex vivo anticoagulant effects in hospitalized patients with cirrhosis.

BACKGROUND: Patients with cirrhosis are at risk of venous thromboembolism (VTE), but strategies for thromboprophylaxis have not been defined. Previous in vitro studies suggest an altered anticoagulant effect of heparins in patients with cirrhosis. OBJECTIVES: To assess the anticoagulant effects of prophylactic low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) doses in patients with cirrhosis in a real-life clinical setting. METHODS: We studied patients with cirrhosis (n = 16) and acute-on-chronic liver failure (ACLF) (n = 14), and compared these with patients without underlying liver disease admitted to non-liver general medical wards (n = 18) and non-liver intensive care units (n = 14), respectively. Blood samples were taken before and 4 h after administration of the first dose of LMWH or UFH. We assessed hemostatic status using thrombin generation assays, thrombin-antithrombin complexes (TAT), and conventional coagulation assays, and included healthy controls (n = 20) to establish reference values. Anti-Xa activity was determined to estimate peak heparin levels. RESULTS: Baseline thrombin generation was similar among all cohorts and healthy controls despite alterations in conventional coagulation assays. On heparin, both absolute and proportional changes of thrombin generation were comparable between all four cohorts (-62% to -85%). TAT levels decreased in all cohorts apart from the ACLF cohort, but did not correlate with the proportional change in thrombin generation. Anti-Xa activity correlated with the proportional change in thrombin generation in patients receiving LMWH, but not in patients receiving UFH. CONCLUSIONS: These data suggest that current prophylactic heparin doses have comparable anticoagulant effects in patients with cirrhosis compared with patients without underlying liver disease.

Prophylactic fresh frozen plasma and platelet transfusion have a prothrombotic effect in patients with liver disease.

BACKGROUND AND AIMS: Patients with liver disease acquire complex changes in their hemostatic system, resulting in prolongation of the international normalized ratio and thrombocytopenia. Abnormalities in these tests are commonly corrected with fresh frozen plasma (FFP) or platelet transfusions before invasive procedures. Whether these prophylactic transfusions are beneficial and truly indicated is increasingly debated. In this study, we studied ex vivo effects of FFP and platelet transfusions in patients with liver disease-associated hemostatic changes in a real-life clinical setting. METHODS: We included 19 patients who were deemed to require prophylactic FFP transfusion by their treating physician and 13 that were prescribed platelet transfusion before a procedure. Hemostatic status was assessed in blood samples taken before and after transfusion and compared with healthy controls (n = 20). RESULTS: Ex vivo thrombin generation was preserved in patients with liver disease before FFP transfusion. Following FFP transfusion, both in and ex vivo thrombin generation significantly increased, as evidenced by a 92% and 38% increase in thrombin-antithrombin and prothrombin fragment 1 + 2 levels, respectively, and a 20% increase in endogenous thrombin potential. Platelet counts increased from 28 [21-41] × 109 /L before to 43 [39-64] × 109 /L after platelet transfusion (P < .01), and was accompanied by increases in in vivo markers of hemostatic activation. CONCLUSIONS: FFP and platelet transfusion resulted in increased thrombin generation and platelet counts in patients with liver disease, indicating a prothrombotic effect. However, whether all transfusions were truly indicated and had a clinically relevant effect is questionable.

Kinetic Models for the Role of Protein Thiols during Oxidation in Beer.

Thiol-containing proteins have been suggested to have antioxidative properties in beer. A kinetic model has been setup for the reactivity of thiols during early stages of oxidative degradation of beer. Kinetic analysis based on the proposed reaction mechanism allowed evaluation of the relative reactivity of beer components, such as bitter acids from hops and polyphenols. The rate constants for the reaction of 1-hydroxyethyl radicals, which are generated during radical mediated oxidation of ethanol in beer, with hop bitter acids and thiols were very similar, and the concentration of these compounds in beer is therefore essential for the relative reactivity. For a standard pilsner beer with 35 international bitter units with typical concentrations of thiols and hop bitter acids, thiols were found to react with ca. 9% of 1-hydroxyethyl radicals, while bitter acids from hops accounted for ca. 88% of the reaction with 1-hydroxyethyl radicals. Polyphenols were not found to account for any major part of the reaction with 1-hydroxyethyl radicals due to low reaction rates and low concentrations in pilsner beer compared to the other components. The kinetic model suggests that the concentration of thiols has to be increased in order to contribute with any significant antioxidative protection and that the fate of thiols during oxidation must be considered since some thiol oxidation products may induce further damage.

Green Tea Polyphenols Decrease Strecker Aldehydes and Bind to Proteins in Lactose-Hydrolyzed UHT Milk.

The effect of epigallocatechin gallate enriched green tea extract (GTE) on flavor, Maillard reactions and protein modifications in lactose-hydrolyzed (LH) ultrahigh temperature (UHT) processed milk was examined during storage at 40 °C for up to 42 days. Addition of GTE inhibited the formation of Strecker aldehydes by up to 95% compared to control milk, and the effect was similar when GTE was added either before or after UHT treatment. Release of free amino acids, caused by proteolysis, during storage was also decreased in GTE-added milk either before or after UHT treatment compared to control milk. Binding of polyphenols to milk proteins was observed in both fresh and stored milk samples. The inhibition of Strecker aldehyde formation by GTE may be explained by two different mechanisms; inhibition of proteolysis during storage by GTE or binding of amino acids and proteins to the GTE polyphenols.

A novel approach for discovering human behavior patterns using unsupervised methods.

BACKGROUND: As is well known, elderly people gradually lose the ability of self-care. The decline can be reflected in changes in their daily life behavior. A solution to assess their health status is to design sensor-enhanced living environments to observe their behavior, in which unobtrusive sensors are usually used. With respect to information extraction from the dataset collected by means of these kinds of sensors, unsupervised methods have to be relied on for practical application. Under the assumption that human lifestyle is associated with health status, this study intends to propose a novel approach to discover behavior patterns using unsupervised methods. METHODS: To evaluate the feasibility of this approach it was applied to datasets collected in the GAL-NATARS study. The study is part of the Lower Saxony research network Design of Environments for Aging (GAL) and conducted in subjects' home environments. The subjects recruited in GAL-NATARS study are older people (age ≥ 70 years), who are discharged from hospital to live alone again at their homes after treatment of a femoral fracture. RESULTS: The change of lifestyle regularity is measured. By analyzing the correlation between the extracted information and medical assessment results of four subjects, two of them exhibited impressive association and the other two showed less association. CONCLUSIONS: The approach may provide complementary information for health assessment; however, the dominant relationship between the change of behavior patterns and the health status has to be shown and datasets from more subjects must be collected in future studies. LIMITATIONS: Merely environmental data were used and no wearable sensor for activity detection or vital parameter measurement is taken into account. Therefore, this cannot comprehensively reflect reality.

Attitudes toward Female Circumcision among Men and Women in Two Districts in Somalia: Is It Time to Rethink Our Eradication Strategy in Somalia?

Somalia has the highest global prevalence (98%) of female circumcision (FC), and, despite a long history of abandonment efforts, it is not clear as to whether or not these programmes have changed people's positive attitudes toward the practice. Against this background, this paper explores the attitudes of Somalis living in Hargeisa and Galkayo districts to the practice of FC. Methods. A purposive sampling of 24 Somalis, including activists and practitioners, men and women, was conducted in Somalia. Unstructured interviews were employed to explore the participants' knowledge of FC, their attitudes toward the continuation/discontinuation of the practice, and the type they want to continue or not to continue. Result. The findings of this qualitative study indicate that there is a strong resistance towards the abandonment of the practice in Somalia. The support for the continuation of Sunna circumcision is widespread, while there is a quite large rejection of Pharaonic circumcision. Conclusion. Therefore, since the "zero tolerance policy" has failed to change people's support for the continuation of the practice in Somalia, programmes that promote the pinch of the clitoral skin and verbal alteration of status, with the goal of leading to total abandonment of FC, should be considered for the Somali context.

Have we made progress in Somalia after 30 years of interventions? Attitudes toward female circumcision among people in the Hargeisa district.

BACKGROUND: Female circumcision is a major public health problem that largely contributes to the ill-health of women and their children globally. Accordingly, the international community is committed to take all possible measures to abolish the practice that is internationally considered to be absolutely intolerable. While the practice is a social tradition shared by people in 28 African countries, there is no country on earth where FC is more prevalent than in Somalia. Yet, since the early 1990s, there is no quantitative study that has investigated whether the perception towards the practice among Somali men and women in Somalia has improved or not. Thus, this cross-sectional quantitative study examines the attitudes toward the practice among people in Hargeisa, Somalia. METHODS: A cross-sectional study of 215 randomly selected persons, including both men and women, was conducted in Hargeisa, Somalia from July to September of 2011. Participants were interviewed using structured questionnaires, with questions including the circumcision status of the female participants, the type of circumcision, if one has the intention to circumcise his/her daughter, whether one supports the continuation or discontinuation of the practice and men's perceptions toward having an uncircumcised woman as a wife. RESULT: The findings show that 97% of the study's participants were circumcised with no age differences. Of this, 81% were subjected to Type 3, while 16% were subjected to either Type 1 or 2 and only 3% were left uncircumcised. Approximately 85% of the respondents had intention to circumcise their daughters, with 13% were planning the most radical form. Among men, 96% preferred to marry circumcised women, whereas overall, 90% of respondents supported the continuation of the practice. The vast majority of the study's respondents had a good knowledge of the negative health effects of female circumcision. In multivariate logistic regressions, with an adjustment for all other important variables, female circumcision (the Sunna form) is a religious requirement 16.5 (2.43-112.6) and the Sunna form is not harmful 25.1(2.35-281.1), are the two factors significantly associated with the continuation of female circumcision. Moreover, females were less likely to support the continuation of FC compared to their male counterparts (aOR 0.07; CI: 0.05-0.88). CONCLUSION: The study shows that the support towards the persistence of the practice is profoundly high in Somalia. People are aware of the health and human rights effect of female circumcision, and yet they support the continuation of the practice. Therefore, over 30 years of campaigns with limited progress demand an alternative approach towards the eradication of female circumcision in Somalia.

[Leadership and change processes in hospitals]. / Endringsledelse i sykehus.

BACKGROUND: Successful change processes in hospitals require leaders with strong competence and personal suitability, who can develop resource efficient and creative solutions. We have investigated how division leaders handle change processes and solve problems that arise in cross-disciplinary meeting activities. MATERIAL AND METHODS: Eight division leaders at two hospitals in the same region of Norway have gone through in-depth interviews about change leadership. RESULTS AND INTERPRETATIONS: Some of the division leaders were familiar with facilitating change processes and used a range of methods and tools, but the majority had limited insight into which methods would be most appropriate in the various phases of a change process. They signalised that the most difficult challenge was to handle interactions dominated by suspicion, negative interpretation, assumptions and hidden agendas. Such interplays were the most limiting factor in the development of a common understanding of demands, goals and commitment to change processes across departments and units.

The development of a semi-preparatory scale supercritical-fluid chromatograph for high-throughput purification of 'combi-chem' libraries.

A unique separator was developed which allowed automatic separation and peak collection using semi-preparative supercritical fluid chromatography (SFC). A peak detector switched the effluent between waste and special collection cassettes. Up to 50 mg of various solutes were injected onto a 21-mm I.D. Cyano column. The entire flow path was contained and no aerosols were generated. Collection efficiency was as high as 95%. Peak purity was often greater than 99. 9%. Typical run times were less than 10 min. An analytical SFC was used to screen the performance of a wide range of mobile and stationary phases for the elution of more than 60 miscellaneous small drug compounds. The best 'universal' gradient employed 0.4% isobutyl or isopropylamine dissolved in methanol, then mixed from 5 to 55% into carbon dioxide at 10%/min. Flow rate was 50 ml/min. The analytical SFC was shown to be a good predictor of the semi-prep instrumental performance.

Capillary gel electrophoresis of single-stranded DNA fragments with UV detection.

Capillary gel electrophoresis has proven to be a powerful tool in biomedical research. We report our investigation of some of the critical parameters affecting separations of single-stranded DNA fragments as monitored by ultraviolet (UV) absorbance detection. Although not as sensitive as laser-induced fluorescence (LIF), UV absorbance detection allows one to calculate quite accurately, and inexpensively, the molarity of each separated DNA fragment and, moreover, the signal "fading" effect normally observed with LIF detection can be, in many cases, substituted for fluorescence to detect the many different single-stranded DNAs, as well as for detection of sequencing reactions.