Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial

Proteome analyses of host membranes modified by intracellular Salmonella enterica Typhimurium

The foodborne, facultative intracellular pathogen Salmonella enterica serovar Typhimurium has the capability to remodel the host endosomal system and establish a network consisting of tubular membranous structures connected with the Salmonella-containing vacuole (SCV). However, despite its ability to form these Salmonella-modified membranes (SMM), the cellular origin and composition of SMM are mostly unknown. Thus we developed a novel approach facilitating the isolation of SMM. Therefore, we combined differential fractionation and affinity-based enrichment using an epitope-tagged SPI2-T3SS effector SseF with liquid chromatography-tandem mass spectrometry (LC-MS/MS). This enabled us to probe the composition of SMM during infection of the epithelial cell line HeLa and mouse macrophage RAW264.7 cells. The identified SMM proteome consists of 247 host proteins in HeLa cells and 262 proteins in macrophages, respectively. The protein compositions revealed the importance of cytoskeletal and host trafficking proteins for SMM and indicated a redirection of host trafficking towards SMM. In addition our results suggested a contribution of the traffic between ER and Golgi apparatus, e.g. COPI and COPII vesicles, that has not been assumed as origin for SMM before. A selection of proteins involved in trafficking and cytoskeleton formation were validated by confocal light microscopy. Furthermore we analysed the effect of IFNgamma activation on the SMM proteome in RAW264.7 macrophages and revealed a strong impact on the protein composition. The identification of IFNgamma-inducible proteins and a higher percentage of ER proteins implied that Salmonella is able to adjust its SMM according to the cell status. Comparison of the SMM proteome with host compartments of other intracellular pathogens indicated communalities that might be important for the biogenesis of pathogen-containing vacuoles despite of their individual replication niches. Furthermore, the methods were adopted for a non-membrane integral Salmonella effector SseJ. Proteome analyses were conducted using the sensitive Velos Orbitrap system. This data set revealed not only the impact of the bait protein during the SMM probing but also differences between MS platforms. Nevertheless, interesting host and Salmonella proteins were identified using this approach, which are starting points for further research. Altogether, this work provides new insights into the origin of Salmonella-modified membranes and serves as a rich source for new theories that will help to understand the biogenesis and function of the Salmonella-containing vacuole and its connected tubular membrane network

Gambling kick or content motivation - what is really initialized by the introduction of software into medical biometry lessons???

Bachground: Teaching statistics to members of non-mathematical disciplines becomes increasingly based on the involvement of interactive learning software. The latter is expected to both increase understanding and motivation and thereby as well studential acceptance. The teaching model implemented at the Medical Biometry Department in Mainz will be used to consider the value of introducing an interactive software like SPSS® into biometry lessons by means of studential evaluations.Methods: After an introductory lecture series, the participants of the Medical Biometry (formerly "Biomathematics") practical courses are requested to solve real data exercises by means of the software SPSS®, where each lessons aims to the derivation of a result synopsis summarizing the results of the performed statistical analyses. In summer 2002 the students of this course were asked to fill out a standardized teaching quality assessment questionnaire on the acceptance of the previous lecture series, the practical course lessons and the involvement of the software.Results: Between the 7 parallel courses the fraction of students reporting "good management with SPSS" varies between 43% and 88% (pooled estimate 58%), but among these students only 30% report a good / very good understanding of the lessons' context and only 15% a good / very good learning effect. Among students with "problems in SPSS management" these fractions both turned out 13%. Among the students with "good management with SPSS", however, 70% considered the understanding during the lecture series as good / very good, 73% reported a good / very good learning effect for the lectures; among the other students both fractions were 13%. These subgrupus only differed significantly for the questionnaire dimension "content motivation" (Likelihood Ratio p<0.001 after correction for teacher effects). Neither the lessons' structure (p=0.362), their relation to the introductory lecture series (p=0.165) nor the teachers' personal and didactical skills (p=0.407) differed significantly between the subgroups of students with and without acceptance of SPSS®.Conclusion: Introduction of a software like SPSS® can only slightly raise studential understanding and subject-associated motivation, but can hardly create them. However, it must be considered by means of independent evaluations, how far these findings can be transferred to the impact of interactive learning tools on students' motivation and acceptance.Hintergrund: Derzeit werden vor allem im Statistik-Unterricht für Anwender zahlreiche interaktive Software- und Lernsysteme entwickelt, von welchen sich neben einer Erhöhung des Verständnisses auch eine Steigerung der Motivation und damit auch der Akzeptanz des Unterrichts bei den Anwendern versprochen wird. Am Mainzer Unterrichtsmodell, welches seit mehreren Jahren die Kurse der Medizinischen Biometrie mit der Software SPSS® durchführt, sollte anhand studentischer Bewertung diese Hoffnung überprüft werden.Methoden: Nach einer vorbereitenden Intensivvorlesung werden im Praktikum der Medizinischen Biometrie (ehemals "Biomathematik") in Mainz von den Studierenden Aufgaben mittels SPSS® bearbeitet, wobei das Ziel jeder Doppelstunde im wesentlichen die Erstellung einer Ergebnissynopse ist. Im Rahmen des Qualitätsmanagements in der Lehre wurden im Sommersemester 2002 von den Studierenden des ersten klinischen Semesters Angaben zur Akzeptanz dieses Kurses, der vorbereitenden Vorlesung und vor allem des den Kurs unterstützenden SPSS® mittels eines standardisierten Evaluationsbogens erhoben.Ergebnisse: Der Anteil Studierender, die nach eigener Einschätzung "gut mit SPSS zurecht gekommen" sind, variiert in den 7 parallelen Kursen zwischen 43% und 88% (gepoolter Anteil 58%). Unter diesen Studierenden berichten jedoch nur 30% ein gutes / sehr gutes Verständnis des Praktikumsstoffes, 15% einen guten / sehr guten Lerneffekt im Praktikum. Unter den Studierenden, die nach eigener Angabe "nicht gut mit SPSS zurecht gekommen" sind, betragen diese Anteile jeweils 13%. Unter den Studierenden, die "gut mit SPSS zurecht gekommen" sind, attestieren ferner 70% der einführenden Vorlesung eine gute / sehr gute Verständlichkeit sowie 73% einen guten / sehr guten Lerneffekt; unter den anderen Studierenden betragen diese Anteile jeweils 66%. Nur im Fragebogen-Aspekt "inhaltliche Motivation" zeigt sich beim Vergleich dieser beiden Gruppen Studierender ein signifikanter Unterschied (Likelihood Ratio p<0.001 nach Korrektur für Kursleitereffekte). Weder für die Struktur des Praktikums (p=0.362), dessen Verknüpfung mit der Vorlesung (p=0.165) noch die Kommunikation und Didaktik (p=0.407) zeigten sich nach Korrektur für Dozenteneffekte nennenswerte Tendenzen zugunsten einer positiveren Bewertung des Kurs bei Akzeptanz von SPSS®.Schlussfolgerung: Mit dem Einbezug einer Software wie SPSS® in den Unterricht können Verständnis und Motivation des für Anwender zumeist schwer zugänglichen Stoffes der Medizinischen Biometrie bestenfalls gesteigert, aber in keinem relevanten Maß geweckt werden. Wie weit diese Erkenntnisse auf explizit für den Unterricht konzipierte Lernsoftware übertragen werden können, muss in unabhängigen Evaluationen überprüft werden

The DGS Corpus Project: Development of a Corpus Based Electronic Dictionary German Sign Language – German

With a target size of 400 hours video from 300 informants, the DGS (German Sign Language) Corpus Project (2009-2023) is the first project that will create a DGS corpus comparable in size to spoken language corpora. In addition to making a large language resource available for research, the project will develop a comprehensive DGS dictionary based on corpus data, significantly advancing state of the art in corpus-based sign language lexicography. Data collection is done with a mobile studio that over the course of three years will be moved to twelve different locations all over Germany. To obtain language data coming as close to natural language use of DGS as possible, two informants coming from the same region interact with each other in a large variety of tasks lasting six hours altogether. The mix of tasks (including warm-ups etc.) is the result of a pilot phase with extensive testing of various elicitation formats and materials. The studio setup was chosen to make the informants feel as comfortable as possible without compromising recording quality. The 7-cameras setup (HD and stereoscopic cameras) promises to deliver videos suitable for manual transcription and image processing that over the course of the project is expected to deliver semi-automatic annotation to increase the effectiveness of the transcription process. As a first step to make the corpus data accessible, translations into German will be produced. The next step is a basic transcription, providing a sign-by-sign segmentation and type-token matching. More detailed transcription (including grammatical information, use of space, eye gaze) will be carried out in a third phase. As limited resources do not allow the whole corpus to be transcribed in detail, it will mainly be the lexicographical workflow determining which parts of the corpus need to be transcribed in detail. Both the transcription and lexicographic work will be carried out within the iLex environment which will steadily be extended over the course of the project in order to make use of synergies with other projects running in parallel (such as Dicta-Sign on semi-automated annotation) or to match new challenges from new linguistic research questions. With more than 20 people working concurrently with corpus data, it is evident that quality assurance has a central role in the project. Intensive transcriber trainings and coding manuals as well as experiments on formalizing inter- and intra-transcriber agreements for coding conventions used (such as HamNoSys) are only the first steps taken. In addition, researchers as well as student coworkers are invited to carry out pilot data experiments on annotation data and metadata to see if data analyses are possible within the existing data model and annotation conventions long before enough data become available to make these studies really feasible. Feedback from these experiments allow us to continually evolve the transcription process and adapt the transcription environment. It is essential for the success of the project that the language community is involved in the project beyond those people participating as informants. The task of contact persons in each region is therefore not limited to finding informants for the data recordings, but also to raise public awareness within the Deaf community. A web portal focusing on the community’s interests in the project (including viewing the corpus video material as a resource for cultural heritage) will also encourage people to provide feedback. In the dictionary context, this might include feedback on individual signs’ regional distribution. Ideas to make this portal not only attractive to contact persons and informants, but to the community at large, include offering consultation hours for questions about the language

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

BackgroundTranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding.MethodsWe did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124.FindingsBetween July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98).InterpretationWe found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial.</div