Death and Liver Transplantation within Two Years of Onset of Drug-Induced Liver Injury

Drug-induced liver injury (DILI) is an important cause of death and indication for liver transplantation (fatality). The role of DILI in these fatalities ispoorly characterized particularly when fatalities occur > 26 weeks after DILI onset. We analyzed patients in the U.S. Drug-Induced Liver Injury Network prospective study having a fatal outcome within 2 years of onset. Each case was reviewed by 8 Network investigators and categorized as DILI having a primary, contributory or no role in the fatality. We subcategorized primary role cases as acute, chronic, acute-on-chronic or acute cholestatic liver failure. For contributory and no role cases, we assigned a primary cause of death. Among 1089 patients, 107 (9.8%) fatalities occurred within 2 years. DILI had a primary role in 68 (64%), a contributory role in 15 (14%) and no role in 22 (21%); 2 had insufficient data. Among primary role cases, 74% had acute, 13% chronic, 7% acute-on-chronic and 6% acute cholestatic failure. For the 15 contributory role cases, common causes of death included sepsis, malignancy and severe cutaneous reactions with multi-organ failure. For the 22 no role cases, malignancies accounted for most fatalities. Higher bilirubin, coagulopathy, leukocytosis and thrombocytopenia were independently associated with DILI fatalities. nR Hy's Law had a higher positive predictive value for overall fatality (14% vs. 10%) and stronger independent association with DILI fatalities within 26 weeks compared to the original version of Hy's Law (HR: 6.2, CI 3.4 – 11.1 vs. 2.2, CI 1.3-3.7). DILI leads directly or indirectly to fatality in 7.6% of cases; 40% of these have non-acute liver failure courses. nR Hy's Law better identifies risk for death compared to the original Hy's Law

A novel high mobility group box 1 neutralizing chimeric antibody attenuates drug-induced liver injury and postinjury inflammation in mice

Acetaminophen (APAP) overdoses are of major clinical concern. Growing evidence underlines a pathogenic contribution of sterile postinjury inflammation in APAP‐induced acute liver injury (APAP‐ALI) and justifies development of anti‐inflammatory therapies with therapeutic efficacy beyond the therapeutic window of the only current treatment option, N‐acetylcysteine (NAC). The inflammatory mediator, high mobility group box 1 (HMGB1), is a key regulator of a range of liver injury conditions and is elevated in clinical and preclinical APAP‐ALI. The anti‐HMGB1 antibody (m2G7) is therapeutically beneficial in multiple inflammatory conditions, and anti‐HMGB1 polyclonal antibody treatment improves survival in a model of APAP‐ALI. Herein, we developed and investigated the therapeutic efficacy of a partly humanized anti‐HMGB1 monoclonal antibody (mAb; h2G7) and identified its mechanism of action in preclinical APAP‐ALI. The mouse anti‐HMGB1 mAb (m2G7) was partly humanized (h2G7) by merging variable domains of m2G7 with human antibody‐Fc backbones. Effector function‐deficient variants of h2G7 were assessed in comparison with h2G7 in vitro and in preclinical APAP‐ALI. h2G7 retained identical antigen specificity and comparable affinity as m2G7. 2G7 treatments significantly attenuated APAP‐induced serum elevations of alanine aminotransferase and microRNA‐122 and completely abrogated markers of APAP‐induced inflammation (tumor necrosis factor, monocyte chemoattractant protein 1, and chemokine [C‐X‐C motif] ligand 1) with prolonged therapeutic efficacy as compared to NAC. Removal of complement and/or Fc receptor binding did not affect h2G7 efficacy. Conclusion: This is the first report describing the generation of a partly humanized HMGB1‐neutralizing antibody with validated therapeutic efficacy and with a prolonged therapeutic window, as compared to NAC, in APAP‐ALI. The therapeutic effect was mediated by HMGB1 neutralization and attenuation of postinjury inflammation. These results represent important progress toward clinical implementation of HMGB1‐specific therapy as a means to treat APAP‐ALI and other inflammatory conditions. (Hepatology 2016;64:1699‐1710)

A record-linkage study of the development of hepatocellular carcinoma in persons with hepatitis C infection in Scotland

We investigated trends in first time hospital admissions and deaths attributable to hepatocellular carcinoma (HCC) in a large population based cohort of 22 073 individuals diagnosed with hepatitis C viral (HCV) infection through laboratory testing in Scotland in 1991 2006. We identified new cases of HCC through record linkage to the national inpatient hospital discharge database and deaths registry. A total of 172 persons diagnosed with HCV were admitted to hospital or died with first time mention of HCC. Hepatocellular carcinoma incidence increased between 1996 and 2006 (average annual change of 6.1, 95% confidence interval (CI):0.9 11.6%, P¼0.021). The adjusted relative risk of HCC was greater for males (hazard ratio¼2.7, 95% CI: 1.7 4.2), for those aged 60 years or older (hazard ratio ¼2.7, 95% CI: 1.9 4.1) compared with 50 59 years, and for those with a previous alcohol related hospital admission (hazard ratio¼2.5, 95% CI: 1.7 3.7). The risk of individuals diagnosed with HCV developing HCC was greatlyincreased compared with the general Scottish population (standardised incidence ratio¼127, 95% CI: 102 156). Owing to the advancing age of the Scottish HCV diagnosed population, the annual number of HCC cases is projected to increase, with a consequent increasing burden on the public healthcare system

Collaborative Learning and Convergence: Library Strategies and Solutions with an Eye on the USG Information Technology Strategic Plan

The article discusses collaborative learning as a library strategy of the University System of Georgia (USG) Information Technology Strategic Plan 2010 and the role of convergence in fostering it. It is stated that collaborative learning enables people to achieve quality learning by way of efficient technologies and its integration with content and environments that will benefit people and institutions. Convergence reportedly refers to the integration of distinct library services that will support the shared purpose of learning

Effects of different matrix representations and connectivity measures on habitat network assessments

Assessing landscape connectivity is important to understand the ecology of landscapes and to evaluate alternative conservation strategies. The question is though, how to quantify connectivity appropriately, especially when the information available about the suitability of the matrix surrounding habitat is limited. Our goal here was to investigate the effects of matrix representation on assessments of the connectivity among habitat patches and of the relative importance of individual patches for the connectivity within a habitat network. We evaluated a set of 50 × 50 km^2 test areas in the Carpathian Mountains and considered three different matrix representations (binary, categorical and continuous) using two types of connections among habitat patches (shortest lines and least-cost paths). We compared connections, and the importance of patches, based on (1) isolation, (2) incidence-functional, and (3) graph measures. Our results showed that matrix representation can greatly affect assessments of connections (i.e., connection length, effective distance, and spatial location), but not patch prioritization. Although patch importance was not much affected by matrix representation, it was influenced by the connectivity measure and its parameterization. We found the biggest differences in the case of the integral index of connectivity and equally weighted patches, but no consistent pattern in response to changing dispersal distance. Connectivity assessments in more fragmented landscapes were more sensitive to the selection of matrix representation. Although we recommend using continuous matrix representation whenever possible, our results indicated that simpler matrix representations can be also used as a proxy to delineate those patches that are important for overall connectivity, but not to identify connections among habitat patches

Systematic Review:Non A-E, seronegative or indeterminate hepatitis; what is this deadly disease?

Background: A significant proportion of cases of acute liver failure (ALF) do not have an identifiable cause; so called “non A-E”, “non-A, non B, non C”, “seronegative” or “indeterminate” hepatitis. However, this entity is clinically not well described.Aim: To collate the known incidence and outcomes in indeterminate hepatitis. This systematic review sought to identify potential aetiologies that ought to be considered, and identify likely future objectives in classification and treatment strategies for indeterminate hepatitis.Methods: Literature review to determine aetiological factors, prevalence and outcomes relating to indeterminate hepatitis.Results: There is significant heterogeneity within the reported cases of indeterminate hepatitis in the literature. Some of the potential infective aetiologies which are reviewed here include; parvovirus B19 (PVB19), herpes simplex virus (HSV), Toga-Like Virus and the Annelloviridae (including SEN-V). Interestingly, this condition predominately affects middle aged women, with subacute progression of the liver failure. In addition, the prognosis of indeterminate hepatitis is poor, with reduced spontaneous survival compared with other causes of acute liver failure and increased need for emergency liver transplantation.Conclusions: Whilst various pathological processes have been implicated in the development of indeterminate hepatitis, the specific cause remains elusive. There is an urgent need for general consensus on a specific definition and exclusion of confounding aetiologies with coordinated multicentre investigation of this rare condition to identify aetiology and develop therapies to reduce the significant mortality and need for emergency liver transplantation associated with this condition

Synthesis, structures and coordination chemistry of singly bridged phosphane-boranes with coordinately unsaturated platinum group metals

A range of singly bridged phosphane-boranes (PBs) have been investigated as potential ligands for basic transition metals. The PBs Ph2PC(Ph)=C(R)BR2 (R = Bu 1, Ph 2, Et 3), based on a rigid cis-ethylene bridges, have been prepared, improving upon limited literature precedent. All three compounds have been comprehensively characterised for the first time, including by X-ray diffraction studies. Significant intramolecular P→B association is apparent in each case, which serves to preclude their engagement as ligands. In contrast, the more flexible PBs R2P(CH2)2BBN (R = Fu 5, Ph 6) readily coordinate to the platinum group metals Pt, Pd and Rh. These complexes have been fully characterised, including an X-ray diffraction study of [Rh(CO){Fu2P(CH2)2-BBN}2Cl] (13)