The bile salt export pump

Canalicular secretion of bile salts mediated by the bile salt export pump Bsep constitutes the major driving force for the generation of bile flow. Bsep is a member of the B-family of the super family of ATP-binding cassette transporters and is classified as ABCB11. Bsep has a narrow substrate specificity, which is largely restricted to bile salts. Bsep is extensively regulated at the transcriptional and posttranscriptional level, which directly modulates canalicular bile formation. Pathophysiological alterations of Bsep by either inherited mutations or acquired processes such as inhibition by drugs or disease-related down regulation may lead to a wide spectrum of mild to severe forms of liver disease. Furthermore, many genetic variants of Bsep are known, some of which potentially render individuals susceptible to acquired forms of liver diseas

Incidence of drug-induced liver injury in medical inpatients

Objectives: Drug-induced liver injury (DILI) is a common concern. However, data on DILI epidemiology in inpatients are sparse. Methods: To investigate the incidence of DILI, we screened all patients in the pharmacoepidemiological inpatient database according to the CIOMS (Council for International Organisation of Medical Science) criteria, which consist of the evaluation of some clinical chemistry laboratory liver parameters (CIOMS laboratory criteria) and the exclusion of any disease-related causes for the liver injury. Thus, only cases with probable or certain causality according to the World Health Organization criteria were included. Results: Among a total of 6383 patients, liver parameters were determined in 4610, and 489 among them fulfilled the CIOMS laboratory criteria. However, 401 patients had to be excluded because of disease-related liver injury and, thus, the study cohort consisted of 4209 patients at risk for DILI. Among a total of 88 DILI cases, 31 had no documented normal baseline liver parameters and, thus, represented prevalent cases. The remaining 57 represented incident DILI cases. Thus, the incidence of DILI was 1.4% (95% CI 1.0, 1.7). The drug classes most frequently causing DILI were heparins, antibacterials, tuberculostatics and antineoplastic agents. Among those, antineoplastic agents and tuberculostatics showed the highest incidence. Liver injury was not mentioned among the diagnoses or in the physician's discharge letter in about 52-68% of all cases. Conclusion: Approximately 1 in 100 patients develops DILI during hospitalisation in a department of medicine. Incidences of DILI were highest for antineoplastic agents and tuberculostatics. DILI is frequently missed and, therefore, DILI detection by diagnoses will result in misleadingly low incidence rate

Asymptomatic Periprosthetic Joint Infection of the Hip with High-Virulence Pathogens: Report of Two Cases

Periprosthetic joint infection (PJI) may be a life-threatening condition, particularly when caused by pathogens with high virulence, capable of developing secondary bloodstream infection. We report two cases of chronic PJI of the hip, one with Staphylococcus aureus in a 27-year-old female with severe anorexia, the other one with Staphylococcus lugdunensis in a 74-year-old female suffering from morbid obesity. Both infections did not cause relevant symptoms over time despite the absence of suppressive antibiotic treatment. To our knowledge, there are no similar cases described in the literature. While it remains difficult to recommend postponing treatment in such cases, this option may be an alternative to suppressive antibiotic therapy

Tutor training to improve first year student transition experience: Focus on graduate attributes

In large first year science subjects, casual tutors deliver up to half of the face-to-face teaching through practical classes and tutorials. A smooth transition for first year students can be influenced by interactions with tutors, particularly through improved engagement with subject content and understanding Graduate Attributes (GAs). Casual tutors may not be aware of the political changes that impact the diversity of students they teach; for example, widening participation strategies mean in science we have students with a greater diversity of backgrounds, knowledge, literacy and numeracy skills. This raises questions of how to support casual tutors to deal with more diversity of student backgrounds. Subject coordinators are encouraged to embed GAs into subject content and assessments. Therefore, tutors need to understand faculty-wide GAs in the context of their discipline to effectively communicate these to students. We ran a training session for casual tutors teaching first year science subjects, to provide information on transition, diversity and faculty-wide GAs. Two follow-up surveys (early and late semester) enabled us to identifying the challenges faced by casual tutors and whether faculty-wide GAs were communicated to students. Future sessions will be tailored to support tutors as they assist our students through their first year transition

Steigerung der Ausschöpfungsquote von Telefonumfragen durch geschickte Einleitungstexte

'In Telefonumfragen wird viel Mühe darauf verwendet, eine möglichst gute Stichprobenausschöpfung zu erreichen. Die Verfasser wenden sich in diesem Beitrag der Frage zu, ob es möglich ist, Einleitungstexte telefonischer Befragungen in der Art und Weise zu variieren, dass die Teilnahmerate gesteigert wird. Zunächst werden Untersuchungsergebnisse zu Ursachen und Einflussfaktoren von Verweigerungen und die Determinanten der Interviewteilnahme referiert. Dann werden zwei Untersuchungsvariablen präsentiert, die sich hinsichtlich einer Teilnahmesteigerung als viel versprechend erweisen: Die Nennung von Auftraggebern der Untersuchung sowie eine in der Einleitung zusätzlich gestellte Frage. Es wird vorhergesagt, dass eine einfach zu beantwortende Frage in der Einleitung, verknüpft mit einer Information, höhere Teilnahmeraten bewirkt. Zusätzlich wird angenommen, dass die Nennung verschiedener Auftraggeber einer Befragung, operationalisiert durch ein Umfrageinstitut, ein Sozialforschungsinstitut und ein Institut im Auftrag einer Universität, ebenfalls zu unterschiedlich hohen Teilnahmeraten führt. Bei einer bundesweit durchgeführten telefonischen Befragung mit einer Zufallsstichprobe von 4.000 Telefonnummern zeigte sich, dass die Einleitungstexte, die die zusätzliche Frage beinhalteten, die Teilnahme signifikant steigerten.' (Autorenreferat)'For telephone surveys much effort is made to maximize cooperation rates. This piece deals with the question of whether varying introduction texts in telephone surveys can increase cooperation rates. After reviewing experimental findings about causes and correlates of refusals in telephone surveys and explaining the determinants of survey participation, two independent variables that seem promising determinants of survey cooperation are identified: the sponsor of the survey and an additional question in the introduction. It was predicted that asking an additional question which was easy to answer and interesting to most people during the introduction, connected with some general information would increase cooperation. In addition it was assumed that referring to differing sponsors of the survey, in this case a survey organization, a social research institute, and a research institute at a university would lead to different cooperation rates. Based on telephone interviews with a random sample of 4.000 telephone numbers all over Germany those introductions that contained the additional question significantly increased cooperation rates.' (author's abstract)

Influence of Physicochemical Characteristics and Stability of Gold and Silver Nanoparticles on Biological Effects and Translocation across an Intestinal Barrier—A Case Study from In Vitro to In Silico

A better understanding of their interaction with cell-based tissue is a fundamental prerequisite towards the safe production and application of engineered nanomaterials. Quantitative experimental data on the correlation between physicochemical characteristics and the interaction and transport of engineered nanomaterials across biological barriers, in particular, is still scarce, thus hampering the development of effective predictive non-testing strategies. Against this background, the presented study investigated the translocation of gold and silver nanoparticles across the gastrointestinal barrier along with related biological effects using an in vitro 3D-triple co-culture cell model. Standardized in vitro assays and quantitative polymerase chain reaction showed no significant influence of the applied nanoparticles on both cell viability and generation of reactive oxygen species. Transmission electron microscopy indicated an intact cell barrier during the translocation study. Single particle ICP-MS revealed a time-dependent increase of translocated nanoparticles independent of their size, shape, surface charge, and stability in cell culture medium. This quantitative data provided the experimental basis for the successful mathematical description of the nanoparticle transport kinetics using a non-linear mixed effects modeling approach. The results of this study may serve as a basis for the development of predictive tools for improved risk assessment of engineered nanomaterials in the future

Antibodies against Platelet Glycoproteins in Clinically Suspected VITT Patients

Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare but severe complication following COVID-19 vaccination, marked by thrombocytopenia and thrombosis. Analogous to heparin-induced thrombocytopenia (HIT), VITT shares similarities in anti-platelet factor 4 (PF4) IgG-mediated platelet activation via the FcγRIIa. To investigate the involvement of platelet-antibodies in VITT, we analyzed the presence of platelet-antibodies directed against glycoproteins (GP)IIb/IIIa, GPV and GPIb/IX in the serum of 232 clinically suspected VITT patients determined based on (suspicion of) occurrence of thrombocytopenia and/or thrombosis in relation to COVID-19 vaccination. We found that 19% of clinically suspected VITT patients tested positive for anti-platelet GPs: 39%, 32% and 86% patients tested positive for GPIIb/IIIa, GPV and GPIb/IX, respectively. No HIT-like VITT patients (with thrombocytopenia and thrombosis) tested positive for platelet-antibodies. Therefore, it seems unlikely that platelet-antibodies play a role in HIT-like anti-PF4-mediated VITT. Platelet-antibodies were predominantly associated with the occurrence of thrombocytopenia. We found no association between the type of vaccination (adenoviral vector vaccine versus mRNA vaccine) or different vaccines (ChAdOx1 nCoV-19, Ad26.COV2.S, mRNA-1273, BTN162b2) and the development of platelet-antibodies. It is essential to conduct more research on the pathophysiology of VITT, to improve diagnostic approaches and identify preventive and therapeutic strategies.</p

Small Cationic DDA:TDB Liposomes as Protein Vaccine Adjuvants Obviate the Need for TLR Agonists in Inducing Cellular and Humoral Responses

Most subunit vaccines require adjuvants in order to induce protective immune responses to the targeted pathogen. However, many of the potent immunogenic adjuvants display unacceptable local or systemic reactogenicity. Liposomes are spherical vesicles consisting of single (unilamellar) or multiple (multilamellar) phospholipid bi-layers. The lipid membranes are interleaved with an aqueous buffer, which can be utilised to deliver hydrophilic vaccine components, such as protein antigens or ligands for immune receptors. Liposomes, in particular cationic DDA:TDB vesicles, have been shown in animal models to induce strong humoral responses to the associated antigen without increased reactogenicity, and are currently being tested in Phase I human clinical trials. We explored several modifications of DDA:TDB liposomes - including size, antigen association and addition of TLR agonists – to assess their immunogenic capacity as vaccine adjuvants, using Ovalbumin (OVA) protein as a model protein vaccine. Following triple homologous immunisation, small unilamellar vesicles (SUVs) with no TLR agonists showed a significantly higher capacity for inducing spleen CD8 IFNγ responses against OVA in comparison with the larger multilamellar vesicles (MLVs). Antigen-specific antibody reponses were also higher with SUVs. Addition of the TLR3 and TLR9 agonists significantly increased the adjuvanting capacity of MLVs and OVA-encapsulating dehydration-rehydration vesicles (DRVs), but not of SUVs. Our findings lend further support to the use of liposomes as protein vaccine adjuvants. Importantly, the ability of DDA:TDB SUVs to induce potent CD8 T cell responses without the need for adding immunostimulators would avoid the potential safety risks associated with the clinical use of TLR agonists in vaccines adjuvanted with liposomes