A Decline in Status 1 Listings: The Impact of Etiology and Medical Management of Acute Liver Failure

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152006/1/lt25638_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152006/2/lt25638.pd

RAMPART (Rapid Anticonvulsant Medication Prior to Arrival Trial): A double‐blind randomized clinical trial of the efficacy of intramuscular midazolam versus intravenous lorazepam in the prehospital treatment of status epilepticus by paramedics

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86836/1/j.1528-1167.2011.03235.x.pd

The Stroke Hyperglycemia Insulin Network Effort (SHINE) trial: an adaptive trial design case study

Background: The \u27Adaptive Designs Accelerating Promising Trials into Treatments (ADAPT-IT)\u27 project is a collaborative effort supported by the National Institutes of Health (NIH) and United States Food & Drug Administration (FDA) to explore how adaptive clinical trial design might improve the evaluation of drugs and medical devices. ADAPT-IT uses the National Institute of Neurologic Disorders & Stroke-supported Neurological Emergencies Treatment Trials (NETT) network as a \u27laboratory\u27 in which to study the development of adaptive clinical trial designs in the confirmatory setting. The Stroke Hyperglycemia Insulin Network Effort (SHINE) trial was selected for funding by the NIH-NINDS at the start of ADAPT-IT and is currently an ongoing phase III trial of tight glucose control in hyperglycemic acute ischemic stroke patients. Within ADAPT-IT, a Bayesian adaptive Goldilocks trial design alternative was developed. Methods: The SHINE design includes response adaptive randomization, a sample size re-estimation, and monitoring for early efficacy and futility according to a group sequential design. The Goldilocks design includes more frequent monitoring for predicted success or futility and a longitudinal model of the primary endpoint. Both trial designs were simulated and compared in terms of their mean sample size and power across a range of treatment effects and success rates for the control group. Results: As simulated, the SHINE design tends to have slightly higher power and the Goldilocks design has a lower mean sample size. Both designs were tuned to have approximately 80% power to detect a difference of 25% versus 32% between control and treatment, respectively. In this scenario, mean sample sizes are 1,114 and 979 for the SHINE and Goldilocks designs, respectively. Conclusions: Two designs were brought forward, and both were evaluated, revised, and improved based on the input of all parties involved in the ADAPT-IT process. However, the SHINE investigators were tasked with choosing only a single design to implement and ultimately elected not to implement the Goldilocks design. The Goldilocks design will be retrospectively executed upon completion of SHINE to later compare the designs based on their use of patient resources, time, and conclusions in a real world setting

Low Serum Hepcidin Is Associated With Reduced Shortâ Term Survival in Adults With Acute Liver Failure

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149282/1/hep30486_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149282/2/hep30486.pd

VWF/ADAMTS13 Imbalance, But Not Global Coagulation or Fibrinolysis, Is Associated With Outcome and Bleeding in Acute Liver Failure

Background and Aims Recent studies of acute liver failure (ALF) in man and animals have suggested that rebalanced hemostasis occurs, with distinct hypercoagulable features clinically evidenced by a low risk of bleeding. Rodent models have shown a link between intrahepatic microthrombus formation and progression of ALF. We sought to confirm these earlier findings in a large series of patients with well-characterized ALF from the Acute Liver Failure Study Group.Approach and Results Citrated plasma samples taken on admission from 676 patients with ALF or acute liver injury (international normalized ratio &gt;= 2.0 without hepatic encephalopathy) were used to determine levels of von Willebrand factor (VWF), a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity, thrombomodulin-modified thrombin generation, and clot lysis time (CLT) and compared with the levels in 40 healthy controls. Patients had 3-fold increased VWF levels, 4-fold decreased ADAMTS13 activity, similar thrombin generating capacity, and 2.4-fold increased CLT, compared with controls. Increasing disease severity was associated with progressively more elevated VWF levels as well as hypofibrinolysis. Patients who died or underwent liver transplantation within 21 days of admission had higher VWF levels, lower ADAMTS13 activity, but similar thrombin generation and a similar proportion of patients with severe hypofibrinolysis, when compared with transplant-free survivors. Likewise, patients with bleeding complications had higher VWF levels and lower ADAMTS13 activity compared to those without bleeding. Thrombin generation and CLT did not differ significantly between bleeding and nonbleeding patients.Conclusions Rebalanced hemostatic status was confirmed in a large cohort of patients with acute liver injury/ALF, demonstrating that VWF/ADAMTS13 imbalance is associated with poor outcome and bleeding. The association between VWF/ADAMTS13 imbalance and bleeding suggests that bleeding in ALF relates more to systemic inflammation than a primary coagulopathy.</p

MTPmle: A SAS Macro and Stata Programs for Marginalized Inference in Semi-Continuous Data

We develop a SAS macro and equivalent Stata programs that provide marginalized inference for semi-continuous data using a maximum likelihood approach. These software extensions are based on recently developed methods for marginalized two-part (MTP) models. Both the SAS and Stata extensions can fit simple MTP models for cross-sectional semi-continuous data. In addition, the SAS macro can fit random intercept models for longitudinal or clustered data, whereas the Stata programs can fit MTP models that account for subject level heteroscedasticity and for a complex survey design. Differences and similarities between the two software extensions are highlighted to provide a comparative picture of the available options for estimation, inclusion of random effects, convergence diagnosis, and graphical display. We provide detailed programming syntax, simulated and real data examples to facilitate the implementation of the MTP models for both SAS and Stata software users

Generation of neutrophil extracellular traps in patients with acute liver failure is associated with poor outcome

Background and Aims: Acute liver failure (ALF) is characterized by significant changes in the hemostatic system and by systemic inflammation. The formation of neutrophil extracellular traps (NETs), in which an activated neutrophil expels its DNA, histones, and granular enzymes, such as myeloperoxidase (MPO), has been associated with immune-mediated and thrombotic diseases. We hypothesized that formation of NETs in patients with ALF contributes to progression of disease. Approach and Results: A total of 676 patients with ALF (international normalized ratio [INR], >= 1.5) or severe acute liver injury (ALI; INR, >= 2.0) were recruited from the U.S. ALF Study Group Registry between 2011 and 2018, of whom 308 patients (45.6%) had acetaminophen-induced ALF. Up to 21 days after admission, 483 patients (71.5%) survived without liver transplantation (LT). Levels of cell-free DNA (cfDNA) and the specific NET marker MPO-DNA complexes were measured in plasma samples obtained on admission and compared to levels in healthy controls. In addition, liver tissue obtained at transplantation of 20 ALF patients was stained for NETs. Levels of cfDNA were 7.1-fold, and MPO-DNA complexes 2.5-fold, higher in patients with ALF compared to healthy controls. cfDNA levels were not associated with 21-day transplant-free survival, but were higher in those patients with more-severe disease on admission, as reflected by various laboratory and clinical parameters. MPO-DNA levels were 30% higher in patients with ALF who died or required urgent LT. Liver tissue of ALF patients stained positive for NETs in 12 of 18 evaluable patients. Conclusions: Here, we provide evidence for NET formation in patients with ALF. Elevated plasma levels of MPO-DNA complexes in patients with ALF were associated with poor outcome, which suggests that NET formation contributes to disease progression

Clinical trialist perspectives on the ethics of adaptive clinical trials: a mixed-methods analysis

Abstract Background In an adaptive clinical trial (ACT), key trial characteristics may be altered during the course of the trial according to predefined rules in response to information that accumulates within the trial itself. In addition to having distinguishing scientific features, adaptive trials also may involve ethical considerations that differ from more traditional randomized trials. Better understanding of clinical trial experts’ views about the ethical aspects of adaptive designs could assist those planning ACTs. Our aim was to elucidate the opinions of clinical trial experts regarding their beliefs about ethical aspects of ACTs. Methods We used a convergent, mixed-methods design employing a 22-item ACTs beliefs survey with visual analog scales and open-ended questions and mini-focus groups. We developed a coding scheme to conduct thematic searches of textual data, depicted responses to visual analog scales on box-plot diagrams, and integrated findings thematically. Fifty-three clinical trial experts from four constituent groups participated: academic biostatisticians (n = 5); consultant biostatisticians (n = 6); academic clinicians (n = 22); and other stakeholders including patient advocacy, National Institutes of Health, and U.S. Food and Drug Administration representatives (n = 20). Results The respondents recognized potential ethical benefits of ACTs, including a higher probability of receiving an effective intervention for participants, optimizing resource utilization, and accelerating treatment discovery. Ethical challenges voiced include developing procedures so trial participants can make informed decisions about taking part in ACTs and plausible, though unlikely risks of research personnel altering enrollment patterns. Conclusions Clinical trial experts recognize ethical advantages but also pose potential ethical challenges of ACTs. The four constituencies differ in their weighing of ACT ethical considerations based on their professional vantage points. These data suggest further discussion about the ethics of ACTs is needed to facilitate ACT planning, design and conduct, and ultimately better allow planners to weigh ethical implications of competing trial designs.http://deepblue.lib.umich.edu/bitstream/2027.42/111302/1/12910_2015_Article_22.pd

The S troke H yperglycemia I nsulin N etwork E ffort ( SHINE ) trial protocol: a randomized, blinded, efficacy trial of standard vs. intensive hyperglycemia management in acute stroke

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102726/1/ijs12045.pd