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Alcohol-related liver disease (ALD) is a major cause of liver-related death worldwide, yet understanding of the three key pathological features of the disease—fibrosis, inflammation and steatosis—remains incomplete. Here, we present a paired liver–plasma proteomics approach to infer molecular pathophysiology and to explore the diagnostic and prognostic capability of plasma proteomics in 596 individuals (137 controls and 459 individuals with ALD), 360 of whom had biopsy-based histological assessment. We analyzed all plasma samples and 79 liver biopsies using a mass spectrometry (MS)-based proteomics workflow with short gradient times and an enhanced, data-independent acquisition scheme in only 3 weeks of measurement time. In plasma and liver biopsy tissues, metabolic functions were downregulated whereas fibrosis-associated signaling and immune responses were upregulated. Machine learning models identified proteomics biomarker panels that detected significant fibrosis (receiver operating characteristic–area under the curve (ROC–AUC), 0.92, accuracy, 0.82) and mild inflammation (ROC–AUC, 0.87, accuracy, 0.79) more accurately than existing clinical assays (DeLong’s test, P C-index of 0.90 and 0.79, respectively. An independent validation cohort reproduced the diagnostic model performance, laying the foundation for routine MS-based liver disease testing.

For years, the use of ketamine as an anesthetic to patients suffering from acute brain injury has been debated because of its possible deleterious effects on the cerebral circulation and thus on the cerebral perfusion. Early studies suggested that ketamine could increase the intracranial pressure thus lowering the cerebral perfusion and hence reduce the oxygen supply to the injured brain. However, more recent studies are less conclusive and might even indicate that patients with acute brain injury could benefit from ketamine sedation. This systematic review summarizes the evidence regarding the use of ketamine in patients suffering from traumatic brain injury. Databases were searched for studies using ketamine in acute brain injury. Outcomes of interest were mortality, intracranial pressure, cerebral perfusion pressure, blood pressure, heart rate, spreading depolarizations, and neurological function. In total 11 studies were included. The overall level of evidence concerning the use of ketamine in brain injury is low. Only two studies found a small increase in intracranial pressure, while two small studies found decreased levels of intracranial pressure following ketamine administration. We found no evidence of harm during ketamine use in patients suffering from acute brain injury.

Background and aimsAlcohol disturbs hepatic lipid synthesis and transport, but the role of lipid dysfunction in the severity of alcohol-related liver disease (ALD) is unclear. We therefore characterised the liver and plasma lipidome in a biopsy-controlled cohort of patients with early ALD.MethodsWe performed ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry for lipidomics of the liver and plasma from 315 patients, and of plasma from 51 healthy controls matched for age, gender and BMI. We correlated lipid levels with histological fibrosis, inflammation and steatosis, after correction for multiple testing and adjustment for age, gender, statin use, BMI, HbA1c, HOMA-IR, and ongoing drinking. Moreover, we investigated the mechanism of dysregulated sphingolipid metabolism by whole-blood transcriptomics and qPCR sequencing of miRNA.ResultsWe detected 198 lipids in the liver and 236 lipids in the circulation from 18 lipid classes. Nearly all ceramides, sphingomyelins and lyso-phosphocholines in plasma decreased as fibrosis progressed. This was paralleled by a comparable decrease in the liver. Circulating and liver sphingomyelins were also inversely associated with hepatic inflammation. The lipidomic signature of healthy controls was only comparable to ALD patients with no fibrosis. Three circulating miRNA, highly involved in sphingomyelin metabolism, were dysregulated together with the mRNA expression of enzymes in the sphingomyelin degradation pathway. Mendelian randomization in Finnish and UK population biobanks externally validated our findings, suggesting a causal relationship between genetic disposition to ALD and low sphingolipid levels.ConclusionsLiver fibrosis severity in alcohol-related liver disease is characterized by selective lipid depletion in blood and liver, indicating profound effects of progressive disease on the bioactive sphingolipids, already from early stages of fibrosis.Visual AbstractHighlightsThe lipidome in the liver and circulation in alcohol-related liver disease (ALD)Sphingolipid, phospholipid and triacylglycerol levels were lowered in fibrosisExpression and regulation of genes in the sphingolipid pathway were affectedALD has a causal link to lowered sphingomyelin levels in bloodLay summaryAlcohol causes a dysfunctional fat metabolism in the liver. In this study, we detected 198 different types of lipids in the liver and 236 in the blood stream of patients with different severity of alcohol-related liver disease. We found that patients with more severe scarring (fibrosis) of the liver, and more severe liver inflammation, had lower levels of sphingolipids both in the circulation and the liver. Sphingolipids regulate cell survival and inflammation, so they may be involved in the mechanism of progressive alcohol-related liver disease.

Alcohol-related liver disease is the most common cause of cirrhosis, and patients are diagnosed at late stages of disease, with high mortality and limited treatment options. However, we have plenty of opportunities to detect alcohol-related liver disease earlier, as most patients have prior contacts with the healthcare system, as discussed in this review. Growing evidence supports algorithms of routine liver blood tests as first-line risk stratification tools, to select which patients could be referred to secondary care for accurate diagnostic testing with liver stiffness measurements or the enhanced liver fibrosis test.

Aims: Alcohol is the leading cause of cirrhosis, but most patients go undetected until decompensation occurs despite frequent contacts with the healthcare system. We aimed to evaluate the diagnostic accuracy of routine liver function tests compared with indirect and direct fibrosis markers and to assess doctors’ abilities to diagnose significant and advanced alcohol-related liver fibrosis. Methods: This study was a retrospective evaluation of liver function tests for diagnosing alcohol-related liver disease compared to indirect fibrosis tests, the ELF test, and transient elastography. We also surveyed nine doctors who were presented with 225 patient cases from a cross-sectional, biopsy-controlled, single-centre study that evaluated diagnostic tools for alcohol-related liver fibrosis. The doctors assessed each case for significant (≥F2) or advanced (≥F3) fibrosis. We assessed inter-rater variability with Fleiss’ kappa. Results: Routine liver function tests had poor diagnostic accuracy (highest area under the ROC curve for platelet count = 0.752) and poor sensitivities (10%–67%) when using the upper or lower normal limits as cut-offs. Indirect fibrosis indices performed significantly better but were still inferior to the ELF test and transient elastography. The nine doctors disagreed substantially in their predictions, with Fleiss’ kappa of 0.24 (95% CI0.22–0.26) and 0.51 (0.44–0.55) for significant and advanced fibrosis. All nine doctors exhibited poor case-finding abilities with sensitivities of 22–93%. Conclusions: When using routine liver function tests, doctors may fail to diagnose more than half of all alcohol-overusing patients with advanced fibrosis, probably because they rely on upper and lower normal limits of routine liver function tests.

Digital technology constitutes a substantial presence in higher education and notions like ‘digital natives’ and ‘21st century digital skills’ dominate educational discourse. However, within the last decade, scholars have started questioning the prevailing techno-optimism and practitioners have started debating whether and how to regulate the use of digital devices. Based on a systematic qualitative analysis of 100 written evaluations and mapping sessions with five students, this study explores students’ experiences in an undergraduate course in which the teacher restricted the use of digital devices in discussion classes. We found that students expressed mostly positive attitudes towards resulting class engagement and mostly negative attitudes towards taking, sharing, and searching their notes. Finally, we discuss our findings based on the notion of media affordances.

In recent years research integrity has received increased attention from scientific governance. Many countries have opened up funding streams for research on (mis)conduct, and a number of international policy efforts have emerged around the topic. In this paper we frame research integrity as a ‘policy object’ and reflect upon how this object is being assembled within one particular context, that of Denmark. Using material from an interview study with actors within Danish research, we outline how policy for research integrity is being imagined and practiced, first describing the diverse actants that are enrolled into the project of ‘research integrity’, and second discussing how responsibility is variously attributed to these. Importantly, we find that despite extensive efforts to define and settle research integrity as policy object, it continues to be assembled in diverse ways in different sites and by different actors. Even in a single national context, ‘research integrity’ remains multiple.

Existing tests for detecting liver fibrosis, inflammation and steatosis, three stages of liver disease that are still reversible are severely hampered by limited accuracy or invasive nature. Here, we present a paired liver-plasma proteomics approach to infer molecular pathophysiology and to identify biomarkers in a cross-sectional alcohol-related liver disease cohort of nearly 600 individuals. Metabolic functions were downregulated whereas fibrosis-associated signaling and novel immune responses were upregulated, but only half of tissue proteome changes were transmitted to the circulation. Machine learning models based on our biomarker panels outperformed existing tests, laying the foundation for a generic proteomic liver health assessment.

Liver elastography gives information on the viscoelastic properties of hepatic tissue-liver stiffness (LS). In contrast, serum markers and imaging techniques provide different information. Information held by circulating biomarkers relate to hepatocellular or biliary damage, inflammation, extracellular matrix remodelling, liver function, or portal hypertension, whereas imaging provides information on structural changes and hepatic hemodynamics. Consequently, the combination of different types of information from elastography, blood tests, and imaging methods may provide knowledge and decision-making power that an individual test cannot provide alone. Algorithms are the mathematical combination of different types of information, either in parallel (at the same time) or sequential (one index test, followed by another test depending on the result of the index test). So far, combining elastography with other biomarkers in multivariable models has only discrete impact on the overall diagnostic accuracy for detecting liver fibrosis and cirrhosis across etiologies. A better approach is to address whether elastography and a serum test are in concordance or discordance. However, while this approach may decrease false positives, there is a risk of placing more patients in a “grey zone” of discordant results, than if using elastography alone. The most promising approach is in primary care, where we may greatly improve case finding while keeping screening costs down, by the systematic use of sequential algorithms with an initial, inexpensive serum test, followed by elastography only in case of a positive screening result. New algorithms will likely be developed using machine-learning techniques and will take advantage of the widespread availability of smartphones and software, with calculating power that is vastly superior to the human brain.

In 2018, the Center for the use of digital technologies in teaching (CIU) in the Vocational Education and Training (VET) sector was launched. The center is funded for three years by the Danish Ministry of Education. The main goals of CIU are to qualify the current use of digital technologies in teaching at the Danish vocational schools and furthermore to create a knowledge base on didactic aspects of technology enhanced teaching environments. The Danish VET sector currently face challenges in terms of recruitment, student retention, personalisation of teaching and learning, and in general to align with the demands of the labor market and industrial partners. The VET sector is characterised by a large degree of heterogeneity, both in terms of educational programmes, teaching practices and student population thus, there are no one-size-fits-all solutions. The Learning Factory model offers a lense to identify and hence solve these challenges while also meeting the goals of CIU. We therefore adopted the Learning Factory model and are now in the process of translating it to fit the Danish VET sector. In this paper, we first outline the process of translating the original Learning Factory model to a Danish VET sector. We then present the first round of Learning Factory established this fall. The five Learning Factories include participants from 21 schools and focus on various uses of IT including Virtual Reality, Augmented Reality, and Learning Management systems. We end with a discussion of how to develop a Learning Factory model that can produce solutions to local authentic problems meanwhile facilitating knowledge-sharing across a large, heterogeneous and complex setting such as the Danish VET sector.

While interdisciplinarity is not a new concept, the political and discursive mobilisation of interdisciplinarity is. Since the 1990s, this movement has intensified, and this has affected central funding bodies so that interdisciplinarity is now a de facto requirement in successful grant application. As a result, the literature is ripe with definitions, taxonomies, discussions and other attempts to grasp and define the concept of interdisciplinarity. In this paper, we explore how strategic demands for interdisciplinarity meet, interact with and change local research practices and results of higher education and research. Our aim is to question and trace the consequences of applying the slippery and difficult term interdisciplinarity in research. The paper is based on ethnographic fieldwork in a Danish interdisciplinary research programme, where we observed and analysed practices of writing, publishing, collaboration and educational development in five different research projects. We show how the call for interdisciplinarity was mobilised in a way that rendered the incentives and motives behind the programme unclear. Furthermore, we argue that the absence of clear definitions and assessment criteria produced a dominant, all-inclusive, but vague, configuration of interdisciplinarity that affected the research outcome, and ultimately, promoted and reproduced the existing monodisciplinary research and power structures.

While the literature concerning doctoral students has looked at institutional setup and socialisation of students within higher education structures and across disciplinary boundaries, so far, litt...

The literature on interdisciplinary higher education is influenced by twooverall trends: one looks at the institutional level of specially designedinterdisciplinary institutions, while the other assesses individualinterdisciplinary educational activities. Much less attention is given tothe processes of creating interdisciplinary education initiatives withintraditional monodisciplinary universities. In this study, we thus explorehow interdisciplinary education and teaching emerge and developwithin universities that have little or no established infrastructure tosupport interdisciplinarity. Using qualitative data from a multi-part casestudy, we examine the development of diverse interdisciplinaryeducational efforts within a traditional faculty-structured university inorder to map the ways in which interdisciplinary educational elementshave been created, supported, challenged or even strengthened by pre-existing monodisciplinary structures. Drawing on theories fromeconomics, literature studies and sociology of education, we concludethat creating interdisciplinary education in such settings demands skillsthat we define as the‘art of managing interstitiality’. The literature on interdisciplinary higher education is influenced by two overall trends: one looks at the institutional level of specially designed interdisciplinary institutions, while the other assesses individual interdisciplinary educational activities. Much less attention is given to the processes of creating interdisciplinary education initiatives within traditional monodisciplinary universities. In this study, we thus explore how interdisciplinary education and teaching emerge and develop within universities that have little or no established infrastructure to support interdisciplinarity. Using qualitative data from a multi-part case study, we examine the development of diverse interdisciplinary educational efforts within a traditional faculty-structured university in order to map the ways in which interdisciplinary educational elements have been created, supported, challenged or even strengthened by pre-existing monodisciplinary structures. Drawing on theories from economics, literature studies and sociology of education, we conclude that creating interdisciplinary education in such settings demands skills that we define as the ‘art of managing interstitiality’.

Formålet med denne artikel er at give undervisere, som er involveret i tværfaglige uddannelser og undervisning, et grundlag for at kunne reflektere over og dis-kutere følgende: Hvad sker der med tværfagligheden i undervisningen, og hvor-dan hænger det sammen med de didaktiske valg i planlægning og udførelse? I artiklen sammenholder og præsenterer forfatterne først de mest udbredte beteg-nelser for tværfaglighed. Ved hjælp af en case bestående af et tværfagligt kursus, udbudt over flere gange og med forskelligt design, peger forfatterne herefter på nogle af de udfordringer, der er forbundet med at praktisere tværfaglig un-dervisning. Artiklen konkluderer, at centrale didaktiske overvejelser om stofud-vælgelse, arbejdsformer, eksamensformer samt deltagerforudsætninger og for-ventninger har afgørende betydning for realiseringen af den tilstræbte tværfag-lighed. This paper looks at questions relevant to the increasing number of teachers involved in interdisciplinary courses at university level. In particular it considers the link between the intended and the realized interdisciplinarity in teaching and how this is related to the didactical planning. Drawing on one case - an interdisciplinary master course offered three times and each time with a new design - the authors highlight some of the challenges associated with interdisciplinary teaching practice. Based on this case, the authors conclude that balancing teacher expectations with possible course outcomes, selecting and organizing course content as well as examination type, all have a massive impact on whether the intended interdisciplinarity is realized over the duration of the course.

Background: Patients with acute exacerbation of chronic obstructive pulmonary disease often require prehospital emergency treatment. This enables patients who are less ill to be treated on-site and to avoid hospital admission, while severely ill patients can receive immediate ventilatory support in the form of intubation. The emergency physician faces difficult treatment decisions, however, and prognostic tools that could assist in determining which patients would benefit from intubation and ventilator support would be helpful. The aim of the current study was to identify prehospital clinical variables associated with mortality from acute exacerbation of chronic obstructive pulmonary disease. As part of the study, we estimated the 30-day mortality for patients with this prehospital diagnosis. Methods: A retrospective study was performed using data collected by the mobile emergency care unit in Odense, Denmark, combined with data from the patients' medical records. Patients with the tentative diagnosis of acute exacerbation of chronic obstructive pulmonary disease between 1st July 2011 and 31st December 2013 were included in the study. Results: Based on data from 530 patients, we found no statistically significant associations between prehospital clinical variables and mortality, apart from a minor association between older age and higher mortality. The overall 30-day mortality was 10%, while that for patients admitted to the intensive care unit was 30%. Conclusion: No specific prehospital prognostic factors for mortality were identified. Prognostic assessment and the decision to withhold treatment for acute exacerbation of chronic obstructive pulmonary disease seem inadvisable in the prehospital setting.

The decision of ‘if and when’ to stop non-selective β-blockers (NSBB) at certain stages of end-stage cirrhosis has been debated intensively and has generated a number of studies with various outcomes.1 ,2 Some studies demonstrated deleterious effects, others improved survival.3 ,4 However, nobody has looked into how these conflicting findings influence doctors and today’s clinical practice when prescribing NSBB. Our hypothesis is that this ongoing controversy causes an unstandardised usage of NSBB depending on the individual clinician. To test this, we performed a survey consisting of 131 branched questions regarding the usage of NSBB in advanced cirrhosis. It was structured with potential contraindications or adverse events and the respondents were asked if they considered these as contraindications or not. Furthermore, they were questioned if NSBB should be reinstituted if the condition improved. The survey was subdivided in a …

BACKGROUND: Early identification and treatment of patients with severe infection improve their prognosis. The aims of this study were to describe the 30-day mortality and to identify prognostic factors among blood-cultured patients in a medical emergency department (MED).PATIENTS AND METHODS: This was a hospital-based cohort study including all adult (≥15 years old) blood-cultured patients at the MED at Odense University Hospital between 1 August 2009 and 31 August 2011.RESULTS: During the study period, 5499/11 988 (45.9%) patients had blood cultures performed within 72 h of arrival and were included in the study. Of those included, 2631 (47.8%) were men, median age 69 years (range 15-103), and 418 (7.6%) were diagnosed with bacteraemia. The overall 30-day mortality among blood-cultured patients was 11.0% (10.2-11.9). In a multivariate Cox regression model, age of more than 80 years [hazard ratio (HR) 4.6 (95% CI 3.6-6.0)], at least two organ failure [HR 3.6 (2.9-4.5)], bacteraemia [HR 1.4 (1.1-1.8)], Charlson Comorbidity Index of at least 2 h [HR 1.7 (1.3-2.0)], SIRS [HR 1.5 (1.2-1.7)], a history of alcohol dependency [HR 1.7 (1.3-2.3)] and late drawing of blood cultures 24-48 h after arrival [HR 1.7 (1.3-2.2)] were found to be prognostic factors of mortality among blood-cultured patients in the MED.CONCLUSION: Among blood-cultured patients in the MED, we found an 11.0% overall 30-day mortality. Factors associated with 30-day mortality were age more than 80 years, at least two organ failure, bacteraemia, Charlson Comorbidity Index of at least 2, SIRS, a history of alcohol dependency and late drawing of blood cultures.

AIM: To propose an allocation system of patients with liver cirrhosis to intensive care unit (ICU), and developed a decision tool for clinical practice.METHODS: A systematic review of the literature was performed in PubMed, MEDLINE and EMBASE databases. The search includes studies on hospitalized patients with cirrhosis and organ failure, or acute on chronic liver failure and/or intensive care therapy.RESULTS: The initial search identified 660 potentially relevant articles. Ultimately, five articles were selected; two cohort studies and three reviews were found eligible. The literature on this topic is scarce and no studies specifically address allocation of patients with liver cirrhosis to ICU. Throughout the literature, there is consensus that selection criteria for ICU admission should be developed and validated for this group of patients and multidisciplinary approach is mandatory. Based on current available data we developed an algorithm, to determine if a patient is candidate to intensive care if needed, based on three scoring systems: premorbid Child-Pugh Score, Model of End stage Liver Disease score and the liver specific Sequential Organ Failure Assessment score.CONCLUSION: There are no established systems for allocation of patients with liver cirrhosis to the ICU and no evidence-based recommendations can be made.

Background It might be a clinical challenge to identify patients with bacteremia. Blood cultures are often ordered based on the symptoms of fever and chills. Detailed knowledge of the clinical presentation of acute medical patients will improve the identification of bacteremic patients. The aim of this study was to evaluate the diagnostic value of temperature (°C), C-reactive-protein (CRP), and Systemic Inflammatory Response Syndrome (SIRS) in bacteremic patients admitted to the Medical Emergency Department (ED).

Background & Aims Alcohol is the most common cause of liver-related mortality and morbidity. We therefore aimed to assess and compare the prognostic performance of elastography and blood-based markers to predict time to the first liver-related event, severe infection, and all-cause mortality in patients with a history of excess drinking. Methods We performed a prospective cohort study in patients with early, compensated alcohol-related liver disease. At baseline, we obtained a liver biopsy, transient elastography (TE), 2-dimensional shear-wave elastography (2D-SWE), enhanced liver fibrosis test (ELF), FibroTest, fibrosis-4 index (FIB-4), non-alcoholic fatty liver fibrosis score (NFS) and Forns index. We compared C-statistics and time-dependent AUC for prognostication. We used validated cut-off points to create 3 risk groups for each test: low, intermediate and high risk. Results We followed 462 patients for a median of 49 months (IQR 31–70). Median age was 57 years, 76% were males, 20% had advanced fibrosis. Eighty-four patients (18%) developed a liver-related event after a median of 18 months (7-34). TE had the highest prognostic accuracy, with a C-statistic of 0.876, and time-dependent AUC at 5 years of 0.889, comparable to 2D-SWE and ELF. TE, ELF and 2D-SWE outperformed FibroTest, FIB4, NFS, Forns index and biopsy-verified fibrosis stage. Compared to patients with TE 15 kPa. Periods of excessive drinking during follow-up increased the risk of progressing to liver-related events, except for patients in the low-risk groups. Conclusion TE, ELF and 2D-SWE are highly accurate prognostic markers in patients with alcohol-related liver disease. Easy-to-use cut-offs can distinguish between substantially different risk profiles. Lay summary Alcohol is the leading cause of death and illness due to liver disease. In this study, we assessed the ability of biomarkers to predict the risk of developing symptomatic liver disease in patients with early stages of alcohol-related liver disease. We found that several tests accurately predicted the risk of liver-related events such as ascites, esophageal varices and hepatic encephalopathy during an average follow-up of 4.1 years. Liver stiffness measurements by ultrasound elastography and the enhanced liver fibrosis test performed best. By using them, we were able to stratify patients into 3 groups with significantly different risks., Graphical abstract, Highlights • 462 patients with compensated ALD experienced 84 liver-related events during a median of 4.1 years of follow-up, and 76 patients died. • Elastography and the ELF test are accurate prognostic tests and outperform biopsy-verified fibrosis stage. • 3-5% of patients with F0-1, liver stiffness by FibroScan 15 kPa, or ELF >10.5. • The hazard ratio for liver-related events was 8 for patients with liver stiffness of 10-15 kPa, and 28 for >15 kPa.

Chronic Obstructive Pulmonary Disease (COPD) is an important and increasing cause of morbidity and mortality worldwide. Patients with COPD suffer from acute exacerbations (AE), which lead to a reduced quality of life, increased risk of mortality, further and longer hospitalization, and increased healthcare costs.