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Aims: Detection and characterization of idiosyncratic drug‐induced liver injury (DILI) currently rely on standard liver tests, which are suboptimal in terms of specificity, sensitivity and prognosis. Therefore, DILI diagnosis can be delayed, with important consequences for the patient. In this study, we aimed to evaluate the potential of osteopontin, cytokeratin‐18 (caspase‐cleaved: ccK18 and total: K18), α‐glutathione‐S‐transferase and microRNA‐122 as new DILI biomarkers. Methods: Serial blood samples were collected from 32 DILI and 34 non‐DILI acute liver injury (ALI) cases and a single sample from 43 population controls without liver injury (HLC) and analysed using enzyme‐linked immunosorbent assay (ELISA) or single‐molecule arrays. Results: All biomarkers differentiated DILI and ALI from HLC with an area under receiver operator characteristic curve (AUC) value of >0.75 but were less efficient in distinguishing DILI from ALI, with ccK18 (0.79) and K18 (0.76) demonstrating highest potential. However, the AUC improved considerably (0.98) for ccK18 when comparing DILI and a subgroup of autoimmune hepatitis cases. Cytokeratin‐18, microRNA‐122 and α‐glutathione‐S‐transferase correlated well with traditional transaminases, while osteopontin correlated most strongly with the international normalized ratio (INR). Conclusions: ccK18 appears promising in distinguishing DILI from autoimmune hepatitis but less so from other forms of acute liver injury. Osteopontin demonstrates prognostic potential with higher levels detected in more severe cases regardless of aetiology. [ABSTRACT FROM AUTHOR]

Background & Aims: No multi‐national prospective study of drug‐induced liver injury (DILI) has originated in Europe. The design of a prospective European DILI registry, clinical features and short‐term outcomes of the cases and controls is reported. Methods: Patients with suspected DILI were prospectively enrolled in the United Kingdom, Spain, Germany, Switzerland, Portugal and Iceland, 2016–2021. DILI cases or non‐DILI acute liver injury controls following causality assessment were enrolled. Results: Of 446 adjudicated patients, 246 DILI patients and 100 had acute liver injury due to other aetiologies, mostly autoimmune hepatitis (n = 42) and viral hepatitis (n = 34). DILI patients (mean age 56 years), 57% women, 60% with jaundice and 3.6% had pre‐existing liver disease. DILI cases and non‐DILI acute liver injury controls had similar demographics, clinical features and outcomes. A single agent was implicated in 199 (81%) DILI cases. Amoxicillin‐clavulanate, flucloxacillin, atorvastatin, nivolumab/ipilimumab, infliximab and nitrofurantoin were the most commonly implicated drugs. Multiple conventional medications were implicated in 37 (15%) and 18 cases were caused by herbal and dietary supplements. The most common single causative drug classes were antibacterials (40%) and antineoplastic/immunomodulating agents (27%). Overall, 13 (5.3%) had drug‐induced autoimmune‐like hepatitis due to nitrofurantoin, methyldopa, infliximab, methylprednisolone and minocycline. Only six (2.4%) DILI patients died (50% had liver‐related death), and another six received liver transplantation. Conclusions: In this first multi‐national European prospective DILI Registry study, antibacterials were the most commonly implicated medications, whereas antineoplastic and immunomodulating agents accounted for higher proportion of DILI than previously described. This European initiative provides an important opportunity to advance the study on DILI. [ABSTRACT FROM AUTHOR]

Among adverse drug reactions, drug-induced liver injury presents particular challenges because of its complexity, and the underlying mechanisms are still not completely characterized. Our knowledge of the topic is limited and based on the assumption that a drug acts on one molecular target. We have leveraged drug polypharmacology, i.e., the ability of a drug to bind multiple targets and thus perturb several biological processes, to develop a systems pharmacology platform that integrates all drug–target interactions. Our analysis sheds light on the molecular mechanisms of drugs involved in drug-induced liver injury and provides new hypotheses to study this phenomenon. [ABSTRACT FROM AUTHOR]

The identification of specific HLA risk alleles in drug‐induced liver injury (DILI) points toward an important role of the adaptive immune system in DILI development. In this study, we aimed to corroborate the role of an adaptive immune response in DILI through immunophenotyping of leukocyte populations and immune checkpoint expressions. Blood samples were collected from adjudicated DILI (n = 12), acute viral hepatitis (VH; n = 13), acute autoimmune hepatitis (AIH; n = 9), and acute liver injury of unknown etiology (n = 15) at day 1 (recognition), day 7, and day >30. Blood samples from patients with nonalcoholic fatty liver disease (NAFLD; n = 20) and healthy liver controls (HLCs; n = 54) were extracted at one time point. Leukocyte populations and immune checkpoint expressions were determined based on cell surface receptors, except for CTLA‐4 that was determined intracellularly, using flow cytometry. At recognition, DILI demonstrated significantly higher levels of activated helper T‐cell (P < 0.0001), activated cytotoxic T‐cells (P = 0.0003), Th1 (P = 0.0358), intracellular CTLA‐4 level in helper T‐cells (P = 0.0192), and PD‐L1 presenting monocytes (P = 0.0452) than HLC. These levels approached those of HLC over time. No significant differences were found between DILI and VH. However, DILI presented higher level of activated helper T‐cells and CTLA‐4 than NAFLD and lower PD‐L1 level than AIH. Our findings suggest that an adaptive immune response is involved in DILI in which activated CD4+ and CD8+ play an important role. Increased expression of negative immune checkpoints is likely the effect of peripheral tolerance regulation. [ABSTRACT FROM AUTHOR]

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. Cases were identified, diagnosed and followed prospectively. Clinical features, drug information and outcome data were collected. 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%). 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. 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. [Display omitted] • Clinical parameters can help predict DILI phenotype and outcome. • Older patients with cytolitic DILI and those with liver disease have worse outcome. • Serum AST at DILI onset should be assessed as it strongly predicts poor outcome. • Prognostic potential of Hy's law in DILI varies between causative agents. [ABSTRACT FROM AUTHOR]

Background and Aims: Drug‐induced liver injury (DILI) presents with a wide phenotypic spectrum requiring an extensive differential diagnosis. Hepatitis E virus (HEV) is not systematically ruled out during acute hepatitis assessment in Spain. The aims of this study were to establish the role of HEV infection and its phenotypic presentation in patients initially suspected of DILI and to determine the anti‐HEV seroprevalence rate. Methods: An analysis of 265 patients with suspected DILI and considered for enrolment in the Spanish DILI Registry and 108 controls with normal liver profiles was undertaken. Anti‐HEV Immunoglobulin (Ig) G antibodies were analysed in serum from all subjects. In those with serum samples extracted within 6 months from liver damage onset (n = 144), HEV antigen (Ag) and anti‐HEV IgM antibodies were tested in duplicate by ELISA. In addition, RT‐PCR was performed externally in eight patients. Results: Out of 144 patients, 12 (8%) were positive for anti‐HEV IgM, mean age was 61 years. Underlying hepatic diseases (OR = 23.4, P <.001) and AST peak >20 fold upper limit of normal (OR = 10.9, P =.002) were associated with the diagnosis of acute hepatitis E. The overall anti‐HEV IgG seroprevalence rate was 35%, evenly distributed between patients with suspected DILI (34%), and controls (39%). Conclusions: HEV seroprevalence and acute hepatitis E rates are relatively high in Spain. A search for active HEV infection is therefore advised in patients assessed for suspicion of DILI, particularly in patients with underlying liver diseases and high transaminase levels. [ABSTRACT FROM AUTHOR]

Drug induced liver injury (DILI) is a relatively rare hepatic condition in response to the use of medications, illegal drugs, herbal products or dietary supplements. It occurs in susceptible individuals through a combination of genetic and environmental risk factors believed to modify drug metabolism and/or excretion leading to a cascade of cellular events, including oxidative stress formation, apoptosis/necrosis, haptenization, immune response activation and a failure to adapt. The resultant liver damage can present with an array of phenotypes, which mimic almost every other liver disorder, and varies in severity from asymptomatic elevation of liver tests to fulminant hepatic failure. Despite recent research efforts specific biomarkers are not still available for routine use in clinical practice, which makes the diagnosis of DILI uncertain and relying on a high degree of awareness of this condition and the exclusion of other causes of liver disease. Diagnostic scales such as the CIOMS/RUCAM can support the causality assessment of a DILI suspicion, but need refinement as some criteria are not evidence-based. Prospective collection of well-vetted DILI cases in established DILI registries has allowed the identification and validation of a number of clinical variables, and to predict a more severe DILI outcome. DILI is also in need of properly designed clinical trials to evaluate the efficacy of new DILI treatments as well as older drugs such as ursodeoxycholic acid traditionally used to ameliorate cholestasis or corticosteroids now widely tried in the oncology field to manage the emergent type of hepatotoxicity related to immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Summary: Background: Nonsteroidal anti‐inflammatory drugs (NSAIDs) are a leading cause of drug‐induced liver injury (DILI) across the world. Ibuprofen is one of the most commonly used and safest NSAIDs, nevertheless reports on ibuprofen‐induced hepatotoxicity are available. Aim: To analyse previously published information on ibuprofen‐induced liver injury for a better characterisation of its phenotypic expression. Method: A systematic search was performed and information on ibuprofen‐induced liver injury included in case series and case reports, in terms of demographic, clinical, biochemical and outcome data, was analysed. Results: Twenty‐two idiosyncratic ibuprofen hepatotoxicity cases were identified in the literature, suggesting a very low prevalence of this type of DILI. These patients had a mean age of 31 years and 55% were females. Mean cumulative dose of ibuprofen and time to onset were 30 g and 12 days, respectively. Hepatocellular injury was the most frequently involved liver injury pattern. Six cases developed vanishing bile duct syndrome. Full recovery occurred in 11 patients after a mean time of 14 weeks, whereas five cases evolved to acute liver failure leading to death/liver transplantation. Conclusions: When assessing potential hepatotoxicity cases, physicians should keep in mind that ibuprofen has been associated with hepatotoxicity in the literature. Ibuprofen‐associated DILI presents commonly as hepatocellular damage after a short latency period. Published reports on ibuprofen hepatotoxicity leading to liver failure resulting in liver transplantation or death are available. However, due to the apparent low absolute risk of ibuprofen‐induced liver complications, ibuprofen can be regarded as an efficacious and safe NSAID. [ABSTRACT FROM AUTHOR]

Carbamazepine (CBZ) causes life‐threating T‐cell‐mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug‐induced liver injury (CBZ‐DILI). In order to evaluate shared or phenotype‐specific genetic predisposing factors for CBZ hypersensitivity reactions, we performed a meta‐analysis of two genomewide association studies (GWAS) on a total of 43 well‐phenotyped Northern and Southern European CBZ‐SCAR cases and 10,701 population controls and a GWAS on 12 CBZ‐DILI cases and 8,438 ethnically matched population controls. HLA‐A*31:01 was identified as the strongest genetic predisposing factor for both CBZ‐SCAR (odds ratio (OR) = 8.0; 95% CI 4.10–15.80; P = 1.2 × 10−9) and CBZ‐DILI (OR = 7.3; 95% CI 2.47–23.67; P = 0.0004) in European populations. The association with HLA‐A*31:01 in patients with SCAR was mainly driven by hypersensitivity syndrome (OR = 12.9; P = 2.1 × 10−9) rather than by Stevens‐Johnson syndrome/toxic epidermal necrolysis cases, which showed an association with HLA‐B*57:01. We also identified a novel risk locus mapping to ALK only for CBZ‐SCAR cases, which needs replication in additional cohorts and functional evaluation. [ABSTRACT FROM AUTHOR]

Background & Aims: Most patients with drug‐induced liver injury (DILI) manifest clinical symptoms while on therapy, while some patients manifest days or weeks after drug cessation (delayed onset). This challenges DILI causality assessment and diagnosis. Factors contributing to the delayed onset phenotype are currently unknown. We explored factors contributing to delayed onset of DILI by analysing culprit drug properties, host factors and their interactions in a large patient population from the Spanish DILI Registry. Methods: Clinical information from 388 patients (69 presented delayed onset) and drug properties of 43 causative drugs (45 active ingredients) were analysed. A two‐tier regression‐based model was used to assess host/drug interactions affecting the probability of delayed onset. Results: Antibacterial and anti‐inflammatory drugs accounted for the delayed onset cases. Drug property of <50% hepatic metabolism (odds ratio [OR] 11.06, 95% confidence interval [95% CI]: 4.4‐32.2, P = 0.0003), daily dose ≥1000 mg (OR: 2.77, 95% CI: 1.3‐6.1, P = 0.0063) and the absence of pre‐existing conditions in a patient (OR: 2.55, 95% CI: 1.3‐4.9, P = 0.0043) were independently associated with delayed onset. The findings were consistent when externally validated using Latin American DILI Network cases (N = 131). Likewise, drug properties of mitochondrial liability and Pauling electronegativity were associated with delayed onset, but dependent on specific host factors such as age, sex and pre‐existing cardiac diseases. Conclusions: This study demonstrated that delayed onset, a specific DILI phenotype, is explained by complex interactions among drug properties and host factors and provided mechanistic hypotheses for future studies. These findings can help improve the diagnostic capability and causality assessment. [ABSTRACT FROM AUTHOR]

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 C epitope C1 (67%) and 3DL1 C Bw4 motif (67%), while 2DL1 C epitope C2 (69%) and 3DL1 C 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. [ABSTRACT FROM AUTHOR]

Despite being relatively rare, drug-induced liver injury (DILI) is a serious condition, both for the individual patient due to the risk of acute liver failure, and for the drug development industry and regulatory agencies due to associations with drug development attritions, black box warnings, and postmarketing withdrawals. A major limitation in DILI diagnosis and prediction is the current lack of specific biomarkers. Despite refined usage of traditional liver biomarkers in DILI, reliable disease outcome predictions are still difficult to make. These limitations have driven the growing interest in developing new more sensitive and specific DILI biomarkers, which can improve early DILI prediction, diagnosis, and course of action. Several promising DILI biomarker candidates have been discovered to date, including mechanistic-based biomarker candidates such as glutamate dehydrogenase, high-mobility group box 1 protein and keratin-18, which can also provide information on the injury mechanism of different causative agents. Furthermore, microRNAs have received much attention lately as potential non-invasive DILI biomarker candidates, in particular miR-122. Advances in "omics" technologies offer a new approach for biomarker exploration studies. The ability to screen a large number of molecules (e.g., metabolites, proteins, or DNA) simultaneously enables the identification of 'toxicity signatures,' which may be used to enhance preclinical safety assessments and disease diagnostics. Omics-based studies can also provide information on the underlying mechanisms of distinct forms of DILI that may further facilitate the identification of early diagnostic biomarkers and safer implementation of personalized medicine. In this review, we summarize recent advances in the area of DILI biomarker studies. [ABSTRACT FROM AUTHOR]

Idiosyncratic drug-induced liver injury (DILI) caused by xenobiotics (drugs, herbals and dietary supplements) presents with a range of both phenotypes and severity, from acute hepatitis indistinguishable of viral hepatitis to autoimmune syndromes, steatosis or rare chronic vascular syndromes, and from asymptomatic liver test abnormalities to acute liver failure. DILI pathogenesis is complex, depending on the interaction of drug physicochemical properties and host factors. The awareness of risk factors for DILI is arising from the analysis of large databases of DILI cases included in Registries and Consortia networks around the world. These networks are also enabling in-depth phenotyping with the identification of predictors for severe outcome, including acute liver failure and mortality/liver transplantation. Genome wide association studies taking advantage of these large cohorts have identified several alleles from the major histocompatibility complex system indicating a fundamental role of the adaptive immune system in DILI pathogenesis. Correct case definition and characterization is crucial for appropriate phenotyping, which in turn will strengthen sample collection for genotypic and future biomarkers studies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and Aim: The genotype-phenotype interaction in drug-induced liver injury (DILI) is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC) hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases. Methods: High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls. Results: The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7) and B*1801 (P/Pc = 0.008/0.22, OR 2.9) were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0) was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019) and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy’s Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2) and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15) were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07). Conclusions: HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients. [ABSTRACT FROM AUTHOR]

Summary: Diagnosis of drug-induced liver injury (DILI) remains a challenge and eagerly awaits the development of reliable hepatotoxicity biomarkers. Several methods have been developed in order to facilitate hepatotoxicity causality assessments. These methods can be divided into three categories: (1) expert judgement, (2) probabilistic approaches, and (3) algorithms or scales. The last category is further divided into general and liver-specific scales. The Council for International Organizations of Medical Sciences (CIOMS) scale, also referred to as the Roussel Uclaf Causality Assessment Method (RUCAM), although cumbersome and difficult to apply by physicians not acquainted with DILI, is used by many expert hepatologists, researchers, and regulatory authorities to assess the probability of suspected causal agents. However, several limitations of this scale have been brought to light, indicating that a number of adjustments are needed. This review is a detailed timely criticism to alert the readers of the limitations and give insight into what would be needed to improve the scale. Instructions on how to approach DILI diagnosis in practice are provided, using CIOMS as an aid to emphasize the topics to be addressed when assessing DILI cases. Amendments of the CIOMS scale in the form of applying authoritative evidence-based criteria, a simplified scoring system and appropriate weighting given to individual parameters based on statistical evaluations with large databases will provide wider applicability in the clinical setting. [ABSTRACT FROM AUTHOR]

Background & Aims: Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction. Methods: We performed a genome-wide association study using 822,927 single nucleotide polymorphism (SNP) markers from 201 White European and US cases of DILI following AC administration (AC-DILI) and 532 population controls, matched for genetic background. Results: AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with an HLA class II SNP (rs9274407, P = 4.8 × 10−14), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P = 1.1 × 10−4). An independent association was observed in the class I region (rs2523822, P = 1.8 × 10−10), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P = .0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P = 2 × 10−6) and HLA-DQB1*0602 (P = 5 × 10−10) and their interaction (P = .005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of autoimmune-related genes, rs2476601 in the gene PTPN22 was associated (P = 1.3 × 10−4). Conclusions: Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI but have limited utility as predictive or diagnostic biomarkers because of the low positive predictive values. [ABSTRACT FROM AUTHOR]

Summary: A cDNA corresponding to a transcript induced in culture by N starvation, was identified in Colletotrichum gloeosporioides by a differential hybridisation strategy. The cDNA comprised 905 bp and predicted a 215 aa protein; the gene encoding the cDNA was termed CgDN24. No function for CgDN24 could be predicted by database homology searches using the cDNA sequence and no homologues were found in the sequenced fungal genomes. Transcripts of CgDN24 were detected in infected leaves of Stylosanthes guianensis at stages of infection that corresponded with symptom development. The CgDN24 gene was disrupted by homologous recombination and this led to reduced radial growth rates and the production of hyphae with a hyperbranching phenotype. Normal sporulation was observed, and following conidial inoculation of S. guianensis, normal disease development was obtained. These results demonstrate that CgDN24 is necessary for normal hyphal development in axenic culture but dispensable for phytopathogenicity. [Copyright &y& Elsevier]

Abstract: The plant antimicrobial peptide MiAMP1 from Macadamia integrifolia and the yeast killer toxin peptide WmKT from Williopsis mrakii are structural homologues. Comparative studies of yeast mutants were performed to test their sensitivity to these two antimicrobial peptides. No differences in susceptibility to MiAMP1 were detected between wild-type and several WmKT-resistant mutant yeast strains. A yeast mutant MT1, resistant to MiAMP1 but unaffected in its susceptibility to plant defensins and hydrogen peroxide, also did not show enhanced tolerance towards WmKT. It is therefore probable that the Greek key β-barrel structure shared by MiAMP1 and WmKT provides a robust structural framework ensuring stability for the two proteins but that the specific action of the peptides depends on other motifs. [Copyright &y& Elsevier]

Simple Summary: The study of cell features has historically been key for the progress of biological sciences and its relevance remains intact. In recent years, mass cytometry has emerged as a promising and powerful technology, capable of studying multiple parameters of cells in the same sample. Mass cytometry has been quickly applied to many research areas, particularly to the study of the immune system for different purposes, in which the simultaneous analysis of a large number of proteins is crucial. However, despite being a technique that is on the rise, its performance in scientific publications has not yet been evaluated. In this work, a bibliometric methodology known as H-Classics was applied to analyse the most relevant articles, known as highly cited papers (HCPs), and determine the main scientific producers (authors, institutions, and countries) and trends around mass cytometry research field. The results confirmed a high interest and application in immunological studies. The identified HCPs came from prestigious institutions and were published in high impact journals. These results may help researchers to expand their knowledge and to establish new valuable collaborative networks around mass cytometry. Mass cytometry (CyTOF) is a relatively novel technique for the multiparametric analysis of single-cell features with an increasing central role in cell biology, immunology, pharmacology, and biomedicine. This technique mixes the fundamentals of flow cytometry with mass spectrometry and is mainly used for in-depth studies of the immune system and diseases with a significant immune load, such as cancer, autoimmune diseases, and viral diseases like HIV or the recently emerged COVID-19, produced by the SARS-CoV-2 coronavirus. The objective of this study was to provide a useful insight into the evolution of the mass cytometry research field, revealing the knowledge structure (conceptual and social) and authors, countries, sources, documents, and organizations that have made the most significant contribution to its development. We retrieved 937 articles from the Web of Science (2010–2019), analysed 71 Highly Cited Papers (HCP) through the H-Classics methodology and computed the data by using Bibliometrix R package. HCP sources corresponded to high-impact journals, such as Nature Biotechnology and Cell, and its production was concentrated in the US, and specifically Stanford University, affiliation of the most relevant authors in the field. HCPs analysis confirmed great interest in the study of the immune system and complex data processing in the mass cytometry research field. [ABSTRACT FROM AUTHOR]

Background & Aims: Hy's Law, which states that hepatocellular drug-induced liver injury (DILI) with jaundice indicates a serious reaction, is used widely to determine risk for acute liver failure (ALF). We aimed to optimize the definition of Hy's Law and to develop a model for predicting ALF in patients with DILI. Methods: We collected data from 771 patients with DILI (805 episodes) from the Spanish DILI registry, from April 1994 through August 2012. We analyzed data collected at DILI recognition and at the time of peak levels of alanine aminotransferase (ALT) and total bilirubin (TBL). Results: Of the 771 patients with DILI, 32 developed ALF. Hepatocellular injury, female sex, high levels of TBL, and a high ratio of aspartate aminotransferase (AST):ALT were independent risk factors for ALF. We compared 3 ways to use Hy's Law to predict which patients would develop ALF; all included TBL greater than 2-fold the upper limit of normal (×ULN) and either ALT level greater than 3 × ULN, a ratio (R) value (ALT × ULN/alkaline phosphatase × ULN) of 5 or greater, or a new ratio (nR) value (ALT or AST, whichever produced the highest ×ULN/ alkaline phosphatase × ULN value) of 5 or greater. At recognition of DILI, the R- and nR-based models identified patients who developed ALF with 67% and 63% specificity, respectively, whereas use of only ALT level identified them with 44% specificity. However, the level of ALT and the nR model each identified patients who developed ALF with 90% sensitivity, whereas the R criteria identified them with 83% sensitivity. An equal number of patients who did and did not develop ALF had alkaline phosphatase levels greater than 2 × ULN. An algorithm based on AST level greater than 17.3 × ULN, TBL greater than 6.6 × ULN, and AST:ALT greater than 1.5 identified patients who developed ALF with 82% specificity and 80% sensitivity. Conclusions: When applied at DILI recognition, the nR criteria for Hy's Law provides the best balance of sensitivity and specificity whereas our new composite algorithm provides additional specificity in predicting the ultimate development of ALF. [Copyright &y& Elsevier]

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 ⩾1 year 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 ⩽1 year 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. [ABSTRACT FROM AUTHOR]