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A formal framework for the analysis of execution traces collected from distributed systems at run-time is presented. We introduce the notions of event and message traces to capture the consistency of causal dependencies between the elements of a trace. We formulate an approach to property testing where a partially ordered execution trace is modeled by a collection of communicating automata. We prove that the model exactly characterizes the causality relation between the events/messages in the observed trace and discuss the implementation of this approach in SDL, where ObjectGEODE is used to verify properties using model-checking techniques. Finally, we illustrate the approach with industrial case studies. [ABSTRACT FROM AUTHOR]

Background: Diversity competence, diversity itself, and a corresponding awareness of possible (intersectional) discrimination mechanisms have not been anchored in the German National Competence based Learning Objectives Catalogue for Medicine 2.0 (Nationaler Kompetenzbasierter Lernzielkatalog 2.0., NKLM) yet, highlighting a systemic gap in national competency frameworks. We present our first experience with a prospective diversity-specific intervention in medical students to assess its short-term impact on students' diversity acceptance (DA) and to develop actionable recommendations for integrating diversity into medical education., Methods: We designed a prospective cohort study using a control group (CG) and intervention group (IG) design. The IG absolved a five-day diversity-specific intervention (50 h; field trip; seminar). Quantitative data were collected using the validated DWD-O5 scale at baseline (T0), three months (T3), and six months (T6), complemented by qualitative responses (diversity issues in the medical curriculum; perceptions and criticisms) categorized using Mayring's content analysis. Descriptive and non-parametric statistics were performed., Results: Thirty-one medical students (n = 10, IG vs n = 21, CG) were enrolled. The IG demonstrated a short-term improvement in diversity competence (+ 9.72%) across all DWD-O5 factors during the intervention. While scores slightly declined at T6, they remained above baseline levels. 35% (CG) vs. 56% (IG) have experienced discrimination in context of medical studies on their own. Participants in both groups stressed the importance of integrating diversity criteria into curricula at an early stage (100% agreement). Findings revealed three key themes: perceived inadequacies in current curricula, self-reported discrimination experiences, and a strong desire for practical diversity training, such as simulation-based learning., Conclusion: The intervention shows promise as an initial step toward addressing diversity gaps in medical education. By combining historical, cultural, and experiential learning approaches, the program fosters essential competencies such as empathy, self-reflection, and bias recognition. More broadly, sustained improvements in diversity competence require longitudinal integration of diversity training across curricula and systemic reforms to national frameworks like the NKLM. Future research should explore the long-term impact of such interventions and strategies for institutionalizing equity-focused medical education., Competing Interests: Declarations. Ethics approval and consent to participate: Informed consent was obtained from all individual participants included in the study. All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Research Committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This analysis has been approved by the independent Ethics Commission of the Faculty of Medicine of the University of Cologne (no reference number). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background & Aims: Prospective drug-induced liver injury (DILI) registries are important sources of information on idiosyncratic DILI. We aimed to present a comprehensive analysis of 843 patients with DILI enrolled into the Spanish DILI Registry over a 20-year time period., Methods: Cases were identified, diagnosed and followed prospectively. Clinical features, drug information and outcome data were collected., Results: A total of 843 patients, with a mean age of 54 years (48% females), were enrolled up to 2018. Hepatocellular injury was associated with younger age (adjusted odds ratio [aOR] per year 0.983; 95% CI 0.974-0.991) and lower platelet count (aOR per unit 0.996; 95% CI 0.994-0.998). Anti-infectives were the most common causative drug class (40%). Liver-related mortality was more frequent in patients with hepatocellular damage aged ≥65 years (p = 0.0083) and in patients with underlying liver disease (p = 0.0221). Independent predictors of liver-related death/transplantation included nR-based hepatocellular injury, female sex, higher onset aspartate aminotransferase (AST) and bilirubin values. nR-based hepatocellular injury was not associated with 6-month overall mortality, for which comorbidity burden played a more important role. The prognostic capacity of Hy's law varied between causative agents. Empirical therapy (corticosteroids, ursodeoxycholic acid and MARS) was prescribed to 20% of patients. Drug-induced autoimmune hepatitis patients (26 cases) were mainly females (62%) with hepatocellular damage (92%), who more frequently received immunosuppressive therapy (58%)., Conclusions: AST elevation at onset is a strong predictor of poor outcome and should be routinely assessed in DILI evaluation. Mortality is higher in older patients with hepatocellular damage and patients with underlying hepatic conditions. The Spanish DILI Registry is a valuable tool in the identification of causative drugs, clinical signatures and prognostic risk factors in DILI and can aid physicians in DILI characterisation and management., Lay Summary: Clinical information on drug-induced liver injury (DILI) collected from enrolled patients in the Spanish DILI Registry can guide physicians in the decision-making process. We have found that older patients with hepatocellular type liver injury and patients with additional liver conditions are at a higher risk of mortality. The type of liver injury, patient sex and analytical values of aspartate aminotransferase and total bilirubin can also help predict clinical outcomes., Competing Interests: Conflict of interest The authors have no conflict of interest to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: There have been increasing reports of liver injury associated with use of herbal and dietary supplements, likely due to easy access to these products and beliefs among consumers that they are safer or more effective than conventional medications. We aimed to evaluate clinical features and outcomes of patients with herbal and dietary supplement-induced liver injuries included in the Spanish DILI Registry., Methods: We collected and analyzed data on demographic and clinical features, along with biochemical parameters, of 32 patients with herbal and dietary supplement-associated liver injury reported to the Spanish DILI registry from 1994 through 2016. We used analysis of variance to compare these data with those from cases of liver injury induced by conventional drugs or anabolic androgenic steroid-containing products., Results: Herbal and dietary supplements were responsible for 4% (32 cases) of the 856 DILI cases in the registry; 20 cases of DILI (2%) were caused by anabolic androgenic steroids. Patients with herbal and dietary supplement-induced liver injury were a mean age of 48 years and 63% were female; they presented a mean level of alanine aminotransferase 37-fold the upper limit of normal, 28% had hypersensitivity features, and 78% had jaundice. Herbal and dietary supplement-induced liver injury progressed to acute liver failure in 6% of patients, compared with none of the cases of anabolic androgenic steroid-induced injury and 4% of cases of conventional drugs. Liver injury after repeat exposure to the same product that caused the first DILI episode occurred in 9% of patients with herbal and dietary supplement-induced liver injury vs none of the patients with anabolic androgenic steroid-induced injury and 6% of patients with liver injury from conventional drugs., Conclusion: In an analysis of cases of herbal and dietary supplement-induced liver injury in Spain, we found cases to be more frequent among young women than older patients or men, and to associate with hepatocellular injury and high levels of transaminases. Herbal and dietary supplement-induced liver injury is more severe than other types of DILI and re-exposure is more likely. Increasing awareness of the hepatoxic effects of herbal and dietary supplements could help physicians make earlier diagnoses and reduce the risk of serious liver damage., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: Routine medical care in Germany, Austria and Switzerland is being increasingly impacted by the cultural and linguistic diversity of an ever more complex world. Both at home and as part of international student exchanges, medical students are confronted with different ways of thinking and acting in relation to health and disease. Despite an increasing number of courses on cultural competence and global health at German-speaking medical schools, systematic approaches are lacking on how to integrate this topic into medical curricula. Methodological approach: This paper is based on a structured consensus-building process by a multidisciplinary committee composed of faculty and students. In a first step, a qualitative online survey was carried out in order to establish an inventory of definitions and concepts. After the second step, in which a literature search was conducted and definitions of global health and transcultural and intercultural competence were clarified, recommendations were formulated regarding content, teaching and institutional infrastructure. Based on small-group work and large-group discussions, different perspectives and critical issues were compiled using multiple feedback loops that served to ensure quality. Results: An inventory on the national and international level showed that great heterogeneity exists in regard to definitions, teaching strategies, teaching formats and faculty qualification. Definitions and central aspects considered essential to medical education were thus established for the use of the terms "cultural competence" and "global health". Recommendations are given for implementation, ranging from practical realization to qualification of teaching staff and education research. Outlook: High-quality healthcare as a goal calls for the systematic internationalization of undergraduate medical education. In addition to offering specific courses on cultural competence and global health, synergies would be created through the integration of cultural competence and global health content into the curricula of already existing subject areas. The NKLM (the national competence-based catalogue of learning objectives for undergraduate medical education) would serve as a basis for this.

Introduction: Teaching social and communicative competences has become an important part of undergraduate dental education. The aim of this study was to explore the influence of a longitudinal curriculum, addressing social and communication skills, on dental students' attitudes towards learning these skills. Material and methods: Data on the attitudes towards learning communication skills were collected at two German universities and compared in a cross-sectional survey. 397 dental students were included, 175 students attended a longitudinal curriculum addressing social and communicative competences while 222 students did not. The dental students' attitude towards learning communication skills was measured by a German version of the Communication Skills Attitude Scale (CSAS-D). Results: Dental students who participated in a longitudinal communication curriculum had significantly lower negative attitudes towards learning communication skills than students who did not attend such courses. Differences in positive attitudes could not be found. Significant interaction effects were found for the factors gender and section of study: female students in the clinical section of their study who participated in the longitudinal curriculum reported higher positive attitudes and lower negative attitudes compared to female students in the preclinical section of study. Conclusion: The results of this study indicate that a longitudinal curriculum addressing communication skills can enhance positive and reduce negative attitudes towards learning communication skills. More longitudinal data is needed to explore to what extent gender affects development of communication skills and how students' attitudes towards learning communication change in the long run.

Objective: The internationalization of teaching and studying as well as increasing numbers of students with increasingly heterogeneous educational biographies and lifestyles require universities to develop awareness of this diversity and the need for adequate diversity management. For some diversity criteria at least it has been proven that they can influence the individual study success of students. The Dean's Office of the Medical Faculty of the University of Cologne has empirically determined a stable prognosis parameter for study progression on the basis of selected criteria in order to enable early detection of students in need of guidance. This will then be used for targeted, diversity-oriented study guidance. On the one hand a correspondingly adapted guidance offer should take into account individual study progressions. On the other hand, measures to improve the equal opportunities of students with regard to their academic success can be discussed. Methodology: With the help of study progression analyses, study progress of cohorts can be recorded longitudinally. The study progression analysis implemented in the control of faculty teaching serves as a central forecasting and steering tool for the forthcoming concept of diversity-oriented study guidance. The significance measurement of the various features is determined using binary logistic regression analyses. Results: As part of the study progression analyses, the study success rate after the first semester has the strongest influence on the concordance with the minimum duration of study in the pre-clinical phase, followed by the characteristics age at commencement of studies and place of university entrance qualification. The school leaving grade only just misses the required significance level of p <0.05. As a predictor gender provides no explanatory contribution in the considered model. Conclusion: In order to do justice to the heterogeneity among the students, university administrators and lecturers should understand the recognition of diversity as a cross-cutting task and keep an eye on diversity-related aspects and discrimination-critical topics for different target groups as well as individual guidance services in the context of individual study guidance. Within the scope of this study, we were able to empirically prove the stable prognosis parameter study success rate after the first semester allows reliable detection of students in need of guidance. The explanatory contribution is larger than any of the individual criteria examined in this study. The specific causes that led to a delay in studying will be analyzed in the context of downstream and diversity-oriented study guidance. A follow-up study will deal with the question of whether the success of students requiring study guidance can be significantly improved by subsequent study guidance.

Objectives: Positive autoantibody (AAB) titres are commonly encountered in autoimmune hepatitis (AIH) and in a proportion of drug-induced liver injury (DILI) patients. The underlying mechanism for selective AAB occurrence in DILI is unknown, but could be associated with variations in immune-associated genes. Hence, we aimed to analyse human leucocyte antigen (HLA) allele compositions in DILI with positive (+) and negative (-) AAB titres and in AIH patients., Methods: High-resolution genotyping of HLA class I (A, B, C) and II (DRB1, DQB1) loci was performed on 207 DILI and 50 idiopathic AIH patients and compared with 885 healthy Spanish controls., Results: Compared with controls, HLA-B*08:01 [44 vs. 9.7%, P=3.7E-13/corrected P-value (Pc)=1.0E-11], C*07:01 (46 vs. 24%, P=6.4E-04/Pc=0.012), DRB1*03:01 (58 vs. 21.5%, P=5.0E-09/Pc=1.0E-07) and DQB1*02:01 (56 vs. 22%, P=6.8E-08/Pc=9.0E-07) were significantly more frequent in AIH patients. The HLA-A*01:01 frequency was increased in the same population, but did not reach significance after Bonferroni's correction (34 vs. 19%, P=0.02/Pc=0.37). Fifty-eight of 207 DILI patients presented positive titres for at least one AAB (predominantly antinuclear antibody 76% and antismooth muscle antibody 28%). There was a tendency towards higher representation of DRB1*14:01 and DQB1*05:03 in DILI AAB+ compared with DILI AAB- (13.8 vs. 4.0%, P=0.02/Pc=0.5; 13.8 vs. 4.7%, P=0.04/Pc=0.5)., Conclusion: The presence of HLA alleles B*08:01, C*07:01, DRB1*03:01, DQB1*02:01 and possibly A*01:01 enhances the risk of AIH (type 1) in Spanish patients. These alleles form part of the ancestral haplotype 8.1. HLA-DRB1*14:01 and DQB1*05:03 could potentially increase the risk of positive AAB (particularly antinuclear antibody) in Spanish DILI patients.

Background & Aims: Chronic outcome following acute idiosyncratic drug-induced liver injury (DILI) is not yet defined. This prospective, long-term follow-up study aimed to analyze time to liver enzyme resolutions to establish the best definition and risk factors of DILI chronicity., Methods: 298 out of 850 patients in the Spanish DILI registry with no pre-existing disease affecting the liver and follow-up to resolution or ⩾1year were analyzed. Chronicity was defined as abnormal liver biochemistry, imaging test or histology one year after DILI recognition., Results: Out of 298 patients enrolled 273 (92%) resolved ⩽1year from DILI recognition and 25 patients (8%) were chronic. Independent risk factors for chronicity were older age [OR: 1.06, p=0.011], dyslipidemia [OR: 4.26, p=0.04] and severe DILI [OR: 14.22, p=0.005]. Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TB) median values were higher in the chronic group during follow-up. Values of ALP and TB >1.1 x upper limit of normal (xULN) and 2.8 xULN respectively, in the second month from DILI onset, were found to predict chronic DILI (p<0.001). Main drug classes involved in chronicity were statins (24%) and anti-infectives (24%). Histological examination in chronic patients demonstrated two cases with ductal lesion and seven with cirrhosis., Conclusions: One year is the best cut-off point to define chronic DILI or prolonged recovery, with risk factors being older age, dyslipidemia and severity of the acute episode. Statins are distinctly related to chronicity. ALP and TB values in the second month could help predict chronicity or very prolonged recovery., Lay Summary: Drug-induced liver injury (DILI) patients who do not resolve their liver damage during the first year should be considered chronic DILI patients. Risk factors for DILI chronicity are older age, dyslipidemia and severity of the acute episode. Chronic DILI is not a very common condition; normally featuring mild liver profile abnormalities and not being an important clinical problem, with the exception of a small number of cases of early onset cirrhosis., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Natural killer cells are an integral part of the immune system and represent a large proportion of the lymphocyte population in the liver. The activity of these cells is regulated by various cell surface receptors, such as killer Ig-like receptors (KIR) that bind to human leukocyte antigen (HLA) class I ligands on the target cell. The composition of KIR receptors has been suggested to influence the development of specific diseases, in particularly autoimmune diseases, cancer and reproductive diseases. The role played in idiosyncratic drug-induced liver injury (DILI) is currently unknown. In this study, we examined KIR gene profiles and HLA class I polymorphisms in amoxicillin-clavulanate (AC) DILI patients in search for potential risk associations. One hundred and two AC DILI patients and 226 controls were genotyped for the presence or absence of 16 KIR loci, including the two pseudogenes 2DP1 and 3DP1. No significant differences were found in the distribution of individual KIRs between patients and controls, which were comparable to previously reported KIR data from ethnically similar cohorts. The 21.6 and 21.2% of the patients and controls, respectively, were homozygous haplotype A carriers, while 78.4 and 78.8%, respectively, contained at least one B haplotype (Bx). The genotypes translated into 27 (AC DILI) and 46 (controls) different gene profiles, with 19 being present in both groups. The most frequent Bx gene profile containing KIRs 2DS2, 2DL2, 2DL3, 2DP1, 2DL1, 3DL1, 2DS4, 3DL2, 3DL3, 2DL4, and 3PD1 was present in 16% of the DILI patients and 14% of the controls. The distribution of HLA class I epitopes did not differ significantly between AC DILI patients and controls. The most frequent receptor-ligand combinations in the DILI patients were 2DL3 + epitope C1 (67%) and 3DL1 + Bw4 motif (67%), while 2DL1 + epitope C2 (69%) and 3DL1 + Bw4 motif (69%) predominated in the controls. This is to our knowledge the first analysis of KIR receptor-HLA ligand associations in DILI, although our findings do not support evidence of these genetic variations playing a major role in AC DILI development.

Objectives: Since 2009, the University of Cologne has been developing a longitudinal curriculum for teaching social and communicative skills to dental students (LSK-Dent) based on the recommendations of the Association for Dental Education in Europe (ADEE). As a part of this curriculum it was considered to develop a reception service in the undergraduate treatment courses of the Department of Operative Dentistry and Periodontology involving the organizational and administrative handling of the patients by the students. Students should gain an insight into everyday practice and the reception service should function as a learning environment for social und communicative competences. This article introduces the LSK-Dent project, the implementation of the reception service and presents initial evaluation results., Methods: Patients (n=575) and students (n=53) filled out a questionnaire. Additionally, four semi-structured interviews with students were conducted., Results: The reception service was successfully implemented and endorsed by the students. First indications suggest that the reception service was well received by students as a learning environment for social und communicative competences and viewed as an opportunity to gain an insight into everyday practice., Conclusion: The reception service is an innovative addition to the treatment courses and an example for transforming an already existing reality in a course into a new learning environment for students. To what extent the implementation of reflexive elements can increase the subjectively perceived additional benefit by students, has to be addressed in further studies.

Background and Aim: Capsule endoscopy and double balloon enteroscopy are well-recognized procedures in obscure gastrointestinal bleeding, with many factors that may influence their diagnosis yield. The aim of the present study was to characterize the degree of agreement between both techniques with focus on the type of lesion in a large cohort of patients at a referral center., Material and Method: One thousand two hundred and nine capsules were administered in 1,078 patients and 381 enteroscopies were performed in 361 patients with obscure-gastrointestinal bleeding from 2004 to 2014., Results: Both procedures were carried out in 332 patients (mean age: 65.22 +/- 15.41, 183 men) and they have a similar diagnosis yield (70.5% vs. 69.6%, p = 0.9). Overall enteroscopy diagnosis yield was higher within patients with a previous positive capsule endoscopy (79.3% vs. 27.9%, p < 0.001). The degree of agreement was very good for polyps (0.89 [95% CI: 0.78-0.99]), good for vascular lesions (0.66 [95% CI: 0.55-0.77]) and tumors(0.66 [95% CI: 0.55-0.76]) and moderate for ulcers (0.56 [95% CI: 0.46-0.67]). Diverticula (0.39 [95% CI: 0.29-0.5]) achieved a fair agreement. The results of CE and DBE differed in 73 patients (22%)., Conclusions: The present study confirms that although overall diagnostic yield by capsule endoscopy and double-balloon enteroscopy is similar, there are many factors which can modify these values, mainly the type of lesion.

Objective: For motor handicapped persons, the use of computer interface devices could be a challenging task. Two research venues have been explored to address the usability problem for handicapped users of computer systems. In the first, the focus is on development of new peripheral devices to accommodate the needs of such users. The second venue, which is the focus of this article, addresses the development of efficient rehabilitation algorithms that can adapt existing interface devices to commands from handicapped users. The main goal of this article is to analyze the existing software adaptation platform PLatform to Evaluate ICT for Assistance with a focus on evaluating and enhancing the use of pointing devices for increased adaptation to interface commands., Subjects and Methods: In the first part of this article, a new quantitative analysis approach is presented, which is useful to occupational therapists in choosing among existing information and communication technologies. We define quantification indicators to be used in the analysis of a person's movements. The proposed indicators would be classified in two categories: Task indicators and adaption indicators. In the second part of the article, we present a fuzzy rehabilitation complementary module that adapts the user command without the need to adjust the interface device. The subject is a quadriplegic 12-year-old boy. The test was conducted using five attempts after a brief description and a small demonstration of the experiment. The test was rerun the second day for another five attempts., Results: The subject could not command the joystick in the left direction without a customized device. With a customized device, he was able to control properly the mouse cursor on the screen., Conclusions: The adaptation technique used in this work helped the subject to properly control the computer pointing device. The evaluation technique helped assess the subject and give the proper parameters to the adaptation algorithm.

Attentional mechanisms allow the brain to selectively allocate its resources to stimuli of interest within the huge amount of information reaching its sensory systems. The voluntary component of attention, endogenous attention, can be allocated in a flexible manner depending on the goals and strategies of the observer. On the other hand, the reflexive component, exogenous attention, is driven by the stimulus. Here, we investigated how exogenous attention is deployed to moving stimuli that form distinct perceptual groups. We showed that exogenous attention is deployed according to a reference frame that moves along with the stimulus. Moreover, in addition to the cued stimulus, exogenous attention is deployed to all elements forming a perceptual group. These properties provide a basis for the efficient deployment of exogenous attention under ecological viewing conditions.

Background and Aims: Flawed ABC transporter functions may contribute to increased risk of drug-induced liver injury (DILI). We aimed to analyse the influence of genetic variations in ABC transporters on the risk of DILI development and clinical presentations in a large Spanish DILI cohort., Methods: A total of ten polymorphisms in ABCB1 (1236T>C, 2677G>T,A, 3435T>C), ABCB4 (1954A>G) and ABCC2 (-1774G>del, -1549A>G, -24C>T, 1249G>A, 3972C>T and 4544G>A) were genotyped using Taqman 5' allelic discrimination assays or sequencing in 141 Spanish DILI patients and 161 controls. The influence of specific genotypes, alleles and haplotypes on the risk of DILI development and clinical presentations was analysed., Results: None of the individual polymorphisms or haplotypes was found to be associated with DILI development. Carriers homozygous for the ABCC2 -1774del allele were however only found in DILI patients. Hence, this genotype could potentially be associated with increased risk, though its low frequency in our Spanish cohort prevented a final conclusion. Furthermore, carriers homozygous for the ABCC2 -1774G/-1549A/-24T/1249G/3972T/4544G haplotype were found to have a higher propensity for total bilirubin elevations when developing DILI., Conclusions: Our findings do not support a role for the analysed polymorphisms in the ABCB1, ABCB4 and ABCC2 transporter genes in DILI development in Spanish patients. The ABCC2 -1774deldel genotype was however restricted to DILI cases and could potentially contribute to enhanced DILI susceptibility.

Objectives: The hepatotoxic potential of statins is controversial. The objectives of this study were to describe the relative frequency of hepatotoxicity caused by statins and the phenotypes found in Spain., Patients and Methods: The incidence of hepatotoxicity attributed to statins in the Spanish Hepatotoxicity Registry (REH) were studied and compared with those attributed to other drugs., Results: Between April 1994 and August 2012, the REH included a total of 858 cases of which 47 (5.5 %) were attributed to statins. Of these, 16 were due to atorvastatin (34 %); 13 to simvastatin (27.7 %); 12 to fluvastatin (25.5 %); 4 to lovastatin (8.5 %) and 2 to pravastatin (4.3 %). Statins represented approximately half of the cardiovascular group which occupied 3rd place (10 %), after anti-infectious agents (37 %) and central nervous system drugs (14 %). The hepatocellular pattern was predominant, especially in the simvastatin group (85%), the cholestatic/mixed pattern was more frequent with fluvastatin (66 %) and had a similar distribution to atorvastatin. Patients with statin-induced toxicity were older (62 years versus 53 years, p < 0.001) and more often demonstrated anautoimmune hepatitis phenotype (8.5 % versus 1.4 %, p < 0.003)., Conclusions: Statins are not a common cause of hepatotoxicity in Spain. Atorvastatin is the statin involved in the greatest number of incidents. The liver injury pattern varies among the different statins. The hepatitis phenotype with autoimmune features appears to be a characteristic signature of statin-induced hepatotoxicity.

Background & Aims: Several pharmaceutical compounds have been shown to exert inhibitory effects on the bile salt export pump (BSEP) encoded by the ABCB11 gene. We analysed the combined effect on drug-induced liver injury (DILI) development of the ABCB11 1331T>C polymorphism and the presence of specific chemical moieties, with known BSEP inhibiting properties, in the causative drug., Methods: Genotyping using a TaqMan 5' allelic discrimination assay was performed in 188 Spanish DILI patients, 219 healthy controls and 91 sex-, age- and drug-matched controls. A chemical structure analysis was performed for each individual causative drug., Results: The CC genotype was significantly associated with hepatocellular damage [odds ratio (OR) = 2.1, P = 0.001], particularly in NSAID DILI cases (OR = 3.4, P = 0.007). In addition, the CC genotype was found to be significantly linked to DILI development from drugs causing <50% BSEP inhibition (OR = 1.8, Pc = 0.011). Of the BSEP inhibitory chemical moieties, 59% of the causative drugs contained a carbocyclic system with at least one aromatic ring, corresponding to 61% of the total cases. The C allele was significantly more frequent in DILI cases containing this chemical moiety, which appear to be conditioned on the ABCB11 1331T>C polymorphism in the absence of other BSEP inhibitory structures., Conclusion: Patients carrying the C allele in the ABCB11 1331T>C polymorphism are at increased risk of developing hepatocellular type of DILI, when taking drugs containing a carbocyclic system with aromatic rings., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Multiple instances of DILI in the same patient with drugs of similar structure or function as well as completely unrelated drugs are not well understood and poorly documented. We have sought evidence of the frequency and characteristics of patients who have experienced two DILI episodes due to different drugs., Methods: All cases of DILI systematically collected in the Spanish DILI Registry between 1994 and 2009 were retrieved. Data on demographics, clinical, laboratory and pathological findings, and outcome were analyzed., Results: Nine patients (mean age 67 years, four women) out of 742, 1.21%, had evidence of two DILI episodes caused by different drugs. In four cases DILI was associated with structurally related drugs and in an additional two cases the drugs had a common target. In another case, unrelated antibiotics were implicated. In only two cases, the two drugs/herbals were not related in structure or function. All but one patient exhibited hepatocellular damage. The type of damage was consistent in both DILI episodes. Four cases presented as autoimmune hepatitis (AIH) in the second episode., Conclusions: Multiple episodes of DILI in association with different drugs occur infrequently. In each individual, the type of injury was similar during the two DILI episodes, regardless of the causative drug. Second episodes of DILI are more likely to be associated with features of AIH. It remains uncertain if this is drug-induced unmasking of true AIH or DILI with autoimmune features. These cases illustrate the dilemma faced by clinicians in distinguishing these possibilities., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

We report an unusual chromosome 22q11 deletion associated with an apparent complementary ring chromosome in a phenotypically normal woman with a family medical history of 22q11 deletion. Using peripheral blood samples, conventional karyotyping, Fluorescence In Situ Hybridization (FISH) analysis on metaphase spreads and oligo array-based comparative genomic hybridization (oligo array-CGH) were performed. After conventional cytogenetic examination, the chromosome formula was as follows: 47,XX,+r(?)[16]/46,XX[6]. The FISH analysis revealed that this patient had a rearranged chromosome 22 with decreased centromeric fluorescence intensity and deletion of the 22q11.2 locus. She also had a supernumerary ring chromosome composed of an alpha-satellite centromere of 22 origin and 22q11.2 locus. The oligo array-CGH profile showed a deletion of approximately 4.18 Mb on chromosome 22 with a log 2 intensity ratio mean deviation of the deleted region of about -0.29. The 22q11 deletion associated with a complementary ring chromosome described in our patient could be consistent with a centromere misdivision mechanism, with one chromosomal break occurring in the alpha-satellite array and a second one in the 22q11 locus, a mechanism which has recently been referred to as the McClintock mechanism., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Increased age and female sex are suggested risk factors for drug-induced hepatotoxicity (DILI). We studied the influence of these variables on the propensity to develop DILI, as well as its clinical expression and outcome. All cases of DILI submitted to the Spanish Registry between April 1994 and August 2007 were analyzed. Six hundred three DILI cases (310 men; mean age, 54 years) showed a similar sex distribution, reaching two peaks in the 40- to 49-year-old and 60- to 69-year-old age groups. No cases were recorded in the 20- to 29-year-old group. Patients aged > or =60 years accounted for 46% of the cases, with a male predominance (158 males, 118 females; P= 0.009), as opposed to younger patients. Older age was independently associated with cholestatic type of injury (odds ratio for an age interval for 1 year: 1.024 [95% confidence interval: 1.010-1.038]; male/female ratio, 1:2; P = 0.001) and younger age with hepatocellular damage (odds ratio: 0.983 [95% confidence interval: 0.972-0.994]; female/male ratio, 1:2; P = 0.002). In the mixed group, no age effect was evident. Outcome with fulminant liver failure/liver transplantation was more frequently encountered in women (P < 0.01). conclusion: Neither older age nor female sex are predisposing factors to overall DILI. However, older age is a determinant for cholestatic damage with a male predominance, whereas younger age is associated with cytolytic damage and a female overrepresentation. Women distinctly exhibit the worst outcome. Knowledge of these phenotypic associations could guide differential diagnosis and attribution of causality in DILI.

Introduction: Diagnosis of Gilbert's disease often involves unnecessary testing and patient anxiety. Rifampin test can support the diagnosis; it has been described in short series and lacks standardization in dose, collection times, result presentation and interpretation. Our objective was to compare the response to oral rifampin in a series of patients with Gilbert's disease, 2 and 4 h after drug administration., Patients and Methods: Eighty-nine patients with Gilbert's disease (elevated total bilirubin with no hepatopathy or hemolysis) were recruited. After a basal blood collection, 900 mg rifampin were administered per os and new samples were drawn 2 and 4 h later. Total and esterified bilirubin were measured in every sample. Haptoglobin concentration was also analyzed., Results: When expressed as relative increase with respect to basal values, variations observed 2 h after rifampin intake were all above 15%. A significant correlation (r = 0.902; p = 0.000) was found between relative increases 2 and 4 h after drug administration. No significant variations were found in haptoglobin concentrations., Conclusion: Rifampin test is useful in diagnosing Gilbert's disease, but variations in total bilirubin concentrations (basal and post-rifampin) make that no absolute cut-off value can be used. Correlation between 2- and 4-h relative increases suggests that a shortened version could simplify the test.

Aim: To evaluate the utility of double-balloon enteroscopy for small-bowel disease., Design: A prospective study of 50 consecutive enteroscopies performed from December 2004 to July 2005 to analyze diagnoses and treatments., Patients: 44 patients (33 had undergone a previous capsule endoscopy) with indications for obscure digestive hemorrhage, angiodysplasia, Peutz-Jeghers syndrome, ulcer, suspected Crohn's disease, tumors, and refractory celiac disease., Results: We carried out enteroscopy studies in 44 patients by the oral route and, in 6 additional patients, by both the oral and anal routes. We reached the ileon with the oral route in all cases but one (jejunal stenosis), and in 4 cases out of 7 with the anal route, with an average duration of 73 minutes. We found angiodysplasia in 19 cases, as well as NSAID-related enteropathy, Crohn's disease, diverticulosis, and Waldenström's disease. We performed biopsies in 31% of cases with diagnoses of adenocarcinoma, lymphangiectasia secondary to tumor in celiac disease, and Whipple's disease. We treated 19 patients with angiodysplasia (1 to 20 synchronous lesions) with argon, and 4 patients with polyps using polipectomy (sporadic polyps or Peutz-Jeghers syndrome). A retained capsule in one patient with stenosis was removed., Conclusions: Double-balloon enteroscopy is a useful and effective technique in the diagnosis and treatment of small intestine diseases, thus complementing capsule endoscopy. More studies are needed to analyze its impact on the management of this condition.

We present the case of a 33-year-old woman who complained of intermittent diarrhea over the previous 8 years and who was diagnosed with common variable immunodeficiency. The woman presented antral atrophic gastritis, partial atrophy of the duodenal villi, nodular lymphoid hyperplasia of the small intestine and lymphocytic colitis. We also review the literature.

Hypercoagulability is a extraintestinal manifestation of inflammatory bowel disease, which could provoke thromboembolic phenomena. Central nervous system venous thrombosis is a rare complication and could be unnoticed. We report on a patient with ulcerative colitis who presented cerebral venous sinus thrombosis as the first manifestation of a hypercoagulable state. We review the literature and discuss about the pathogenic mechanisms of such complication.

During blunt abdominal trauma the small bowel and/or its mesentery may be injured; if abdominal trauma occurs after compression by an incorrectly-applied seat belt, underlying viscera may be crushed between the vertebral and the seat belt; ischemia or infarction of the intestinal wall, and delayed fibrosis and stenosis may occur. We present a patient, operated on two months after blunt abdominal trauma, with small bowel obstruction secondary to post-traumatic intestinal fibrosis. Assuming that this condition is rarely suspected, a delayed diagnosis and treatment of these patients may occur.