The Contents of Herbal and Dietary Supplements Implicated in Liver Injury in the United States Are Frequently Mislabeled

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149508/1/hep41346_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149508/2/hep41346.pd

Early phonological and sociocognitive skills as predictors of later language and social communication outcomes

Background:  Previous studies of outcome for children with early language delay have focused on measures of early language as predictors of language outcome. This study investigates whether very early processing skills (VEPS) known to underpin language development will be better predictors of specific language and social communication outcomes than measures of language itself. Method:  Participants were 163 children referred to clinical services with concerns about language at 2;6–3;6 years and followed up at 4–5 years. Novel assessments of phonological and sociocognitive processing were administered at Time 1 (T1), together with a standardised test of receptive and expressive language, and parental report of expressive vocabulary. The language test was re-administered at Time 2 (T2), together with assessments of morphosyntax and parental reports of social communication. Results:  Intercorrelations at and between T1 and T2 were high, and dissociations were rare. Ordinal regressions were run, entering predictors singly and simultaneously. With the exception of the phonological task, every early measure on its own was significantly predictive of most outcomes, and receptive language was the strongest all-round predictor. Results of simultaneous entry, controlling for the effect of other predictors, showed that early language was the strongest predictor of general language outcome, but early phonology was the strongest predictor of a measure of morphosyntax, and early sociocognition the strongest predictor of social communication. Conclusions:  Language measures which draw on a wide range of skills were the strongest overall predictors of general language outcomes. However, our VEPS measures were stronger predictors of specific outcomes. The clinical and theoretical implications of these findings are discussed

Causality Assessment for Suspected DILI During Clinical Phases of Drug Development

Causality assessment is a critical step in establishing the diagnosis of drug induced liver injury (DILI) during drug development. DILI may resemble almost any type of liver disease, and often presents a serious challenge to clinical investigators and drug makers. The diagnosis of DILI is largely based upon a combination of a compatible clinical course, exclusion of all other reasonable causes, resemblance of clinical and pathological features to known features of liver injury due to the drug (i.e., “drug’s signature”), and incidence of liver injury among patients treated with the drug compared to placebo or comparator. Causality assessment for suspected DILI is currently performed using either evaluation by physicians with expertise in liver disorders (i.e., expert opinion) or standardized scoring instruments such as the Roussel Uclaf Causality Assessment Method (RUCAM). Both approaches are widely used in the post marketing setting. Causality assessment based on expert opinion is considered superior to standardized instruments such as RUCAM, in the setting of drug development, and is currently the preferred approach during clinical trials. There is a need for a systematic revision of RUCAM that will render it more suitable for the setting of clinical trials and drug development. Careful monitoring and meticulous data collection during clinical trials are essential in all cases with established liver injury to allow for a proper causality assessment. A workshop was convened to discuss best practices for the assessment of drug-induced liver injury (DILI) in clinical trials. This publication is based on the conclusions of this workshop

Liver injury from herbals and dietary supplements in the U.S. Drug‐Induced Liver Injury Network

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108649/1/hep27317.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/108649/2/hep27317-sup-0001-supptbl1.pd

Reliability of the Roussel Uclaf Causality Assessment Method for assessing causality in drug-induced liver injury

The Roussel Uclaf Causality Assessment Method (RUCAM) was developed to quantify the strength of association between a liver injury and the medication implicated as causing the injury. However, its reliability in a research setting has never been fully explored. The aim of this study was to determine test-retest and interrater reliabilities of RUCAM in retrospectively-identified cases of drug induced liver injury. The Drug-Induced Liver Injury Network is enrolling well-defined cases of hepatotoxicity caused by isoniazid, phenytoin, clavulanate/amoxicillin, or valproate occurring since 1994. Each case was adjudicated by three reviewers working independently; after an interval of at least 5 months, cases were readjudicated by the same reviewers. A total of 40 drug-induced liver injury cases were enrolled including individuals treated with isoniazid (nine), phenytoin (five), clavulanate/amoxicillin (15), and valproate (11). Mean ± standard deviation age at protocol-defined onset was 44.8 ± 19.5 years; patients were 68% female and 78% Caucasian. Cases were classified as hepatocellular (44%), mixed (28%), or cholestatic (28%). Test-retest differences ranged from −7 to +8 with complete agreement in only 26% of cases. On average, the maximum absolute difference among the three reviewers was 3.1 on the first adjudication and 2.7 on the second, although much of this variability could be attributed to differences between the enrolling investigator and the external reviewers. The test-retest reliability by the same assessors was 0.54 (upper 95% confidence limit = 0.77); the interrater reliability was 0.45 (upper 95% confidence limit = 0.58). Categorizing the RUCAM to a five-category scale improved these reliabilities but only marginally

Sentence repetition: what does the task measure?

Background: Sentence repetition is gaining increasing attention as a source of information about children's sentence-level abilities in clinical assessment, and as a clinical marker of specific language impairment. However, it is widely debated what the task is testing and therefore how informative it is. Aims: (1) To evaluate the effects of different types of long-term linguistic knowledge on immediate recall, (2) to assess age sensitivity of repetition tasks designed to evaluate these effects, and (3) to establish if the effects are similar across typologically different languages. The study also considers the implications of the findings for the use of sentence repetition as a research and clinical assessment tool. Methods & Procedures: Participants were 50 English-speaking and 50 Czech-speaking typically developing 4–5-year-olds. Children's ability to recall sequences of items was compared in seven linguistic conditions ranging from fully well-formed sentences to sequences of non-words. In each condition, children repeated blocks of successively longer stimuli to establish their span. Outcomes & Results: Results showed significant but differential effects of all linguistic factors in both languages. While syntactic violations and presence of non-words dramatically reduced children's span, semantic implausibility and the removal of sentence prosody played a significant but much smaller role. Familiarity of function words was more important than familiarity of content words. The effects of different linguistic factors on spans were the same for both languages and did not change between 4 and 5 years, although average spans increased over this age range. Conclusions & Implications: Children's ability to repeat sentences is more dependent on their familiarity with morphosyntax and lexical phonology than semantics or prosody, with function words of particular importance. Findings have implications for the use of recall in clinical assessment and as a research tool

Excess mortality in patients with advanced chronic hepatitis C treated with long-term peginterferon

Chronic hepatitis C virus infection can cause chronic liver disease, cirrhosis and liver cancer. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial was a prospective, randomized controlled study of long-term, low-dose peginterferon therapy in patients with advanced chronic hepatitis C who failed to respond to a previous course of optimal antiviral therapy. The aim of this follow-up analysis is to describe the frequency and causes of death among this cohort of patients. Deaths occurring during and after the HALT-C Trial were reviewed by a committee of investigators to determine the cause of death and to categorize each death as liver- or nonliver-related and as related or not to complications of peginterferon. Rates of liver transplantation were also assessed. Over a median of 5.7 years, 122 deaths occurred among 1,050 randomized patients (12%), of which 76 were considered liver-related (62%) and 46 nonliver-related (38%); 74 patients (7%) underwent liver transplantation. At 7 years the cumulative mortality rate was higher in the treatment compared to the control group (20% versus 15%, P = 0.049); the primary difference in mortality was in patients in the fibrosis compared to the cirrhosis stratum (14% versus 7%, P = 0.01); comparable differences were observed when liver transplantation was included. Excess mortality, emerging after 3 years of treatment, was related largely to nonliver-related death; liver-related mortality was similar in the treatment and control groups. No specific cause of death accounted for the excess mortality and only one death was suspected to be a direct complication of peginterferon. Conclusion: Long-term maintenance peginterferon in patients with advanced chronic hepatitis C is associated with an excess overall mortality, which was primarily due to nonliver-related causes among patients with bridging fibrosis. (H EPATOLOGY 2011;)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83750/1/24169_ftp.pd

Hepatotoxicity Due to Hydroxycut: A Case Series

Muscletech Hydroxycut® (Iovate Health Sciences Research, Oakville, Ontario) was a popular weight loss supplement that was recalled by the manufacturer in May 2009 based on reports of hepatotoxicity associated with this supplement

Outcomes in hepatitis C virus–infected recipients of living donor vs. deceased donor liver transplantation

In this retrospective study of hepatitis C virus (HCV)–infected transplant recipients in the 9-center Adult to Adult Living Donor Liver Transplantation Cohort Study, graft and patient survival and the development of advanced fibrosis were compared among 181 living donor liver transplant (LDLT) recipients and 94 deceased donor liver transplant (DDLT) recipients. Overall 3-year graft and patient survival were 68% and 74% in LDLT, and 80% and 82% in DDLT, respectively. Graft survival, but not patient survival, was significantly lower for LDLT compared to DDLT ( P = 0.04 and P = 0.20, respectively). Further analyses demonstrated lower graft and patient survival among the first 20 LDLT cases at each center (LDLT 20; P = 0.002 and P = 0.002, respectively) and DDLT recipients ( P 20 and DDLT were not significantly different ( P = 0.66 and P = 0.74, respectively). Overall, 3-year graft survival for DDLT, LDLT >20, and LDLT 20 were not significantly different. Important predictors of graft loss in HCV-infected patients were limited LDLT experience, pretransplant HCC, and higher MELD at transplantation. Liver Transpl 13:122–129, 2007. © 2006 AASLD.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55915/1/20995_ftp.pd