Implications of pre-transplant sarcopenia and frailty in patients with non-alcoholic steatohepatitis and alcoholic liver disease.

Frailty manifesting as sarcopenia is an independent risk factor for mortality in cirrhosis, and often presents in low model for end-stage liver disease (MELD) patients. Its etiology is multifactorial, but key physiologic changes culminate in altered energy utilization in the fasting state, preferentially utilizing muscle amino acids for gluconeogenesis thereby promoting sarcopenia. Hyperammonemia alters the circulating amino acid profile, diminishing pro-muscle branched-chain amino acids like leucine. The metabolic syndrome worsens sarcopenia through multi-tissue insulin resistance. Alcohol also exacerbates sarcopenia as a direct muscle toxin and inhibitor of growth signaling. Therapy is aimed at alcohol cessation, frequent high-protein meals, branched-chain amino acid supplementation, and diminished time spent fasting. Moderate exercise can improve muscle mass and muscle quality, though precise exercise regimens have not yet been explicitly determined. Studies are ongoing into the effects of myostatin antagonists and insulin sensitizers. The Liver Frailty Index can predict patients most at risk of poor outcome and should be considered in the management of all cirrhotic patients. Specialty testing like dual-energy X-ray absorptiometry (DEXA) scanning and cross-sectional estimates of muscle mass are areas of active research and may play a future role in clinical risk-stratification.

Hepatitis C-positive liver transplantation: outcomes and current practice.

PURPOSE OF REVIEW: The coincidence of the opioid epidemic and the approval of direct-acting antivirals for the treatment of hepatitis C virus (HCV) has resulted in an imbalance in HCV viraemic donors relative to HCV viraemic patients awaiting liver transplantation. Although ethical concerns exist about knowingly infecting patients with HCV in the absence of prospective, protocolized studies, transplantation of HCV-positive liver allografts into HCV-negative recipients has increased exponentially in recent years. For this reason, we sought to review outcomes, cost-effectiveness and ethical concerns associated with this practice. RECENT FINDINGS: Short-term outcomes in terms of patient and graft survival are equivalent to those who received HCV-negative allografts without an increase in acute rejection, biliary or vascular complications. Few cases of treatment failure have been reported and complications related to the virus itself such as fibrosing cholestatic hepatitis and membranous glomerulonephritis are rare and reversible with prompt direct-acting antiretroviral treatment. The practice appears cost-effective and modelling suggests a survival benefit for patients willing to accept HCV-positive organs compared with those who do not. SUMMARY: In light of the preponderance of current data, one could argue it is unethical to withhold HCV-positive grafts from HCV-negative recipients who have undergone thorough informed consent.

Treating HCV in a Captive Audience: Eradication Efforts in the Prison Microenvironment.

Testing for and treating Hepatitis C (HCV) patients in the prison setting is effective in the short term to reducing the overall burden of HCV in the prison microenvironment, with growing evidence that such efforts could yield substantial overall benefits in the effort to eradicate HCV in society. However, rates of reinfection are as yet unknown.

Pharmacokinetic and Chemical Synthesis Optimization of a Potent d-Peptide HIV Entry Inhibitor Suitable for Extended-Release Delivery.

Peptides often suffer from short in vivo half-lives due to proteolysis and renal clearance that limit their therapeutic potential in many indications, necessitating pharmacokinetic (PK) enhancement. d-Peptides, composed of mirror-image d-amino acids, overcome proteolytic degradation but are still vulnerable to renal filtration due to their small size. If renal filtration could be slowed, d-peptides would be promising therapeutic agents for infrequent dosing, such as in extended-release depots. Here, we tether a diverse set of PK-enhancing cargoes to our potent, protease-resistant d-peptide HIV entry inhibitor, PIE12-trimer. This inhibitor panel provides an opportunity to evaluate the PK impact of the cargoes independently of proteolysis. While all the PK-enhancing strategies (PEGylation, acylation, alkylation, and cholesterol conjugation) improved in vivo half-life, cholesterol conjugation of PIE12-trimer dramatically improves both antiviral potency and half-life in rats, making it our lead anti-HIV drug candidate. We designed its chemical synthesis for large-scale production (CPT31) and demonstrated that the PK profile in cynomolgous monkeys supports future development of monthly or less frequent depot dosing in humans. CPT31 could address an urgent need in both HIV prevention and treatment.

Accurate Identification of Fatty Liver Disease in Data Warehouse Utilizing Natural Language Processing.

INTRODUCTION: Natural language processing is a powerful technique of machine learning capable of maximizing data extraction from complex electronic medical records. METHODS: We utilized this technique to develop algorithms capable of "reading" full-text radiology reports to accurately identify the presence of fatty liver disease. Abdominal ultrasound, computerized tomography, and magnetic resonance imaging reports were retrieved from the Veterans Affairs Corporate Data Warehouse from a random national sample of 652 patients. Radiographic fatty liver disease was determined by manual review by two physicians and verified with an expert radiologist. A split validation method was utilized for algorithm development. RESULTS: For all three imaging modalities, the algorithms could identify fatty liver disease with >90% recall and precision, with F-measures >90%. DISCUSSION: These algorithms could be used to rapidly screen patient records to establish a large cohort to facilitate epidemiological and clinical studies and examine the clinic course and outcomes of patients with radiographic hepatic steatosis.

Protease-resistant peptide design-empowering nature's fragile warriors against HIV.

Peptides have great potential as therapeutic agents, but their use is often limited by susceptibility to proteolysis and their resulting in vivo fragility. In this review, we focus on peptidomimetic approaches to produce protease-resistant peptides with the potential for greatly improved clinical utility. We focus on the use of mirror-image (D-peptide) and ß-peptides as two leading approaches with distinct design principles and challenges. Application to the important and difficult problem of inhibiting HIV entry illustrates the current state-of-the-art in peptidomimetic technologies. We also summarize future directions for this field and highlight remaining obstacles to widespread use of protease-resistant peptides.

Design of a modular tetrameric scaffold for the synthesis of membrane-localized D-peptide inhibitors of HIV-1 entry.

The highly conserved HIV-1 gp41 "pocket" region is a promising target for inhibiting viral entry. PIE12-trimer is a protease-resistant trimeric d-peptide inhibitor that binds to this pocket and potently blocks HIV entry. PIE12-trimer also possesses a reserve of binding energy that provides it with a strong genetic barrier to resistance ("resistance capacitor"). Here, we report the design of a modular scaffold employing PEGs of discrete lengths for the efficient optimization and synthesis of PIE12-trimer. This scaffold also allows us to conjugate PIE12-trimer to several membrane-localizing cargoes, resulting in dramatically improved potency and retention of PIE12-trimer's ability to absorb the impact of resistance mutations. This scaffold design strategy should be of broad utility for the rapid prototyping of multimeric peptide inhibitors attached to potency- or pharmacokinetics-enhancing groups.

Design of a potent D-peptide HIV-1 entry inhibitor with a strong barrier to resistance.

The HIV gp41 N-trimer pocket region is an ideal viral target because it is extracellular, highly conserved, and essential for viral entry. Here, we report on the design of a pocket-specific D-peptide, PIE12-trimer, that is extraordinarily elusive to resistance and characterize its inhibitory and structural properties. D-peptides (peptides composed of D-amino acids) are promising therapeutic agents due to their insensitivity to protease degradation. PIE12-trimer was designed using structure-guided mirror-image phage display and linker optimization and is the first D-peptide HIV entry inhibitor with the breadth and potency required for clinical use. PIE12-trimer has an ultrahigh affinity for the gp41 pocket, providing it with a reserve of binding energy (resistance capacitor) that yields a dramatically improved resistance profile compared to those of other fusion inhibitors. These results demonstrate that the gp41 pocket is an ideal drug target and establish PIE12-trimer as a leading anti-HIV antiviral candidate.