Development and First Clinical Use of an Extracorporeal Artificial Multiorgan System in Acute-on-Chronic Liver Failure Patients.

Multiple organ failure (MOF) is a common and deadly condition. Patients with liver cirrhosis with acute-on-chronic liver failure (AOCLF) are particularly susceptible. Excess fluid accumulation in tissues makes routine hemodialysis generally ineffective because of cardiovascular instability. Patients with three or more organ failures face a mortality rate of more than 90%. Many cannot survive liver transplantation. Extracorporeal support systems like MARS (Baxter, Deerfield, IL) and Prometheus (Bad Homburg, Germany) have shown promise but fall short in bridging patients to transplantation. A novel Artificial Multi-organ Replacement System (AMOR) was developed at the University of Washington Medical Center. AMOR removes protein-bound toxins through a combination of albumin dialysis, a charcoal sorbent column, and a novel rinsing method to prevent sorbent column saturation. It removes excess fluid through hemodialysis. Ten AOCLF patients with over three organ failures were treated by the AMOR system. All patients showed significant clinical improvement. Fifty percent of the cohort received liver transplants or recovered liver function. AMOR was successful in removing large amounts of excess body fluid, which regular hemodialysis could not. AMOR is cost-effective and user-friendly. It removes excess fluid, supporting the other vital organs such as liver, kidneys, lungs, and heart. This pilot study's results encourage further exploration of AMOR for treating MOF patients.

Transcutaneous ultrasound-mediated gene delivery into canine livers achieves therapeutic levels of factor VIII expression.

A safe, effective, and inclusive gene therapy will significantly benefit a large population of patients with hemophilia. We used a minimally invasive transcutaneous ultrasound-mediated gene delivery (UMGD) strategy combined with microbubbles (MBs) to enhance gene transfer into 4 canine livers. A mixture of high-expressing, liver-specific human factor VIII (hFVIII) plasmid and MBs was injected into the hepatic vein via balloon catheter under fluoroscopy guidance with simultaneous transcutaneous UMGD treatment targeting a specific liver lobe. Therapeutic levels of hFVIII expression were achieved in all 4 dogs, and hFVIII levels were maintained at a detectable level in 3 dogs throughout the 60-day experimental period. Plasmid copy numbers correlated with hFVIII antigen levels, and plasmid-derived messenger RNA (mRNA) was detected in treated livers. Liver transaminase levels and histology analysis indicated minimal liver damage and a rapid recovery after treatment. These results indicate that liver-targeted transcutaneous UMGD is promising as a clinically feasible therapy for hemophilia A and other diseases.

Fluidic Considerations of Measuring Intracranial Pressure Using an Open External Ventricular Drain.

Measurement of intracranial pressure (ICP) during cerebrospinal fluid (CSF) drainage with an external ventricular drain (EVD) typically requires stopping the flow during measurement. However, there may be benefits to simultaneous ICP measurement and CSF drainage. Several studies have evaluated whether accurate ICP measurements can be obtained while the EVD is open. They report differing outcomes when it comes to error, and hypothesize several sources of error. This study presents an investigation into the fluidic sources of error for ICP measurement with concurrent drainage in an EVD. Our experiments and analytical model both show that the error in pressure measurement increases linearly with flow rate and is not clinically significant, regardless of drip chamber height. At physiologically relevant flow rates (40 mL/hr) and ICP set points (13.6 - 31.3 cmH2O or 10 - 23 mmHg), our model predicts an underestimation of 0.767 cmH2O (0.56 mmHg) with no observed data point showing error greater than 1.09 cmH2O (0.8 mmHg) in our experiment. We extrapolate our model to predict a realistic worst-case clinical scenario where we expect to see a mean maximum error of 1.06 cmH2O (0.78 mmHg) arising from fluidic effects within the drainage system for the most resistive catheter. Compared to other sources of error in current ICP monitoring, error in pressure measurement due to drainage flow is small and does not prohibit clinical use. However, other effects such as ventricular collapse or catheter obstruction could affect ICP measurement under continuous drainage and are not investigated in this study.

Rapid relaxation of pandemic restrictions after vaccine rollout favors growth of SARS-CoV-2 variants: A model-based analysis.

The development and deployment of several SARS-CoV-2 vaccines in a little over a year is an unprecedented achievement of modern medicine. The high levels of efficacy against transmission for some of these vaccines makes it feasible to use them to suppress SARS-CoV-2 altogether in regions with high vaccine acceptance. However, viral variants with reduced susceptibility to vaccinal and natural immunity threaten the utility of vaccines, particularly in scenarios where a return to pre-pandemic conditions occurs before the suppression of SARS-CoV-2 transmission. In this work we model the situation in the United States in May-June 2021, to demonstrate how pre-existing variants of SARS-CoV-2 may cause a rebound wave of COVID-19 in a matter of months under a certain set of conditions. A high burden of morbidity (and likely mortality) remains possible, even if the vaccines are partially effective against new variants and widely accepted. Our modeling suggests that variants that are already present within the population may be capable of quickly defeating the vaccines as a public health intervention, a serious potential limitation for strategies that emphasize rapid reopening before achieving control of SARS-CoV-2.

Controlling long-term SARS-CoV-2 infections can slow viral evolution and reduce the risk of treatment failure.

The rapid emergence and expansion of novel SARS-CoV-2 variants threatens our ability to achieve herd immunity for COVID-19. These novel SARS-CoV-2 variants often harbor multiple point mutations, conferring one or more evolutionarily advantageous traits, such as increased transmissibility, immune evasion and longer infection duration. In a number of cases, variant emergence has been linked to long-term infections in individuals who were either immunocompromised or treated with convalescent plasma. In this paper, we used a stochastic evolutionary modeling framework to explore the emergence of fitter variants of SARS-CoV-2 during long-term infections. We found that increased viral load and infection duration favor emergence of such variants. While the overall probability of emergence and subsequent transmission from any given infection is low, on a population level these events occur fairly frequently. Targeting these low-probability stochastic events that lead to the establishment of novel advantageous viral variants might allow us to slow the rate at which they emerge in the patient population, and prevent them from spreading deterministically due to natural selection. Our work thus suggests practical ways to achieve control of long-term SARS-CoV-2 infections, which will be critical for slowing the rate of viral evolution.

Risk of rapid evolutionary escape from biomedical interventions targeting SARS-CoV-2 spike protein.

The spike protein receptor-binding domain (RBD) of SARS-CoV-2 is the molecular target for many vaccines and antibody-based prophylactics aimed at bringing COVID-19 under control. Such a narrow molecular focus raises the specter of viral immune evasion as a potential failure mode for these biomedical interventions. With the emergence of new strains of SARS-CoV-2 with altered transmissibility and immune evasion potential, a critical question is this: how easily can the virus escape neutralizing antibodies (nAbs) targeting the spike RBD? To answer this question, we combined an analysis of the RBD structure-function with an evolutionary modeling framework. Our structure-function analysis revealed that epitopes for RBD-targeting nAbs overlap one another substantially and can be evaded by escape mutants with ACE2 affinities comparable to the wild type, that are observed in sequence surveillance data and infect cells in vitro. This suggests that the fitness cost of nAb-evading mutations is low. We then used evolutionary modeling to predict the frequency of immune escape before and after the widespread presence of nAbs due to vaccines, passive immunization or natural immunity. Our modeling suggests that SARS-CoV-2 mutants with one or two mildly deleterious mutations are expected to exist in high numbers due to neutral genetic variation, and consequently resistance to vaccines or other prophylactics that rely on one or two antibodies for protection can develop quickly -and repeatedly- under positive selection. Predicted resistance timelines are comparable to those of the decay kinetics of nAbs raised against vaccinal or natural antigens, raising a second potential mechanism for loss of immunity in the population. Strategies for viral elimination should therefore be diversified across molecular targets and therapeutic modalities.