scholarly journals Application of a Biologically Contained Reporter System To Study Gain-of-Function H5N1 Influenza A Viruses with Pandemic Potential

mSphere ◽  
2020 ◽  
Vol 5 (4) ◽  
Author(s):  
Eva E. Spieler ◽  
Eva Moritz ◽  
Silke Stertz ◽  
Benjamin G. Hale
Keyword(s):  
Viral Genome ◽  
Influenza A ◽  
Risk Mitigation ◽  
Genetically Modified ◽  
Influenza Viruses ◽  
Mitigation Strategies ◽  
Wild Type ◽  
Gain Of Function ◽  
Ha Gene ◽  
Risk Mitigation Strategies

ABSTRACT Natural adaptation of an antigenically novel avian influenza A virus (IAV) to be transmitted efficiently in humans has the potential to trigger a devastating pandemic. Understanding viral genetic determinants underlying adaptation is therefore critical for pandemic preparedness, as the knowledge gained enhances surveillance and eradication efforts, prepandemic vaccine design, and efficacy assessment of antivirals. However, this work has risks, as making gain-of-function substitutions in fully infectious IAVs may create a pathogen with pandemic potential. Thus, such experiments must be tightly controlled through physical and biological risk mitigation strategies. Here, we applied a previously described biological containment system for IAVs to a 2009 pandemic H1N1 strain and a highly pathogenic H5N1 strain. The system relies on deletion of the essential viral hemagglutinin (HA) gene, which is instead provided in trans, thereby restricting multicycle virus replication to genetically modified HA-complementing cells. In place of HA, a Renilla luciferase gene is inserted within the viral genome, and a live-cell luciferase substrate allows real-time quantitative monitoring of viral replication kinetics with a high dynamic range. We demonstrate that biologically contained IAV-like particles exhibit wild-type sensitivities to approved antivirals, including oseltamivir, zanamivir, and baloxavir. Furthermore, the inability of these IAV-like particles to genetically acquire the host-encoded HA allowed us to introduce gain-of-function substitutions in the H5 HA gene that promote mammalian transmissibility. Biologically contained “transmissible” H5N1 IAV-like particles exhibited wild-type sensitivities to approved antivirals, to the fusion inhibitor S20, and to neutralization by existing H5 monoclonal and polyclonal sera. This work represents a proof of principle that biologically contained IAV systems can be used to safely conduct selected gain-of-function experiments. IMPORTANCE Understanding how animal influenza viruses can adapt to spread in humans is critical to prepare for, and prevent, new pandemics. However, working safely with pathogens that have pandemic potential requires tight regulation and the use of high-level physical and biological risk mitigation strategies to stop accidental loss of containment. Here, we used a biological containment system for influenza viruses to study strains with pandemic potential. The system relies on deletion of the essential HA gene from the viral genome and its provision by a genetically modified cell line, to which virus propagation is therefore restricted. We show that this method permits safe handling of these pathogens, including gain-of-function variants, without the risk of generating fully infectious viruses. Furthermore, we demonstrate that this system can be used to assess virus sensitivity to both approved and experimental drugs, as well as the antigenic profile of viruses, important considerations for evaluating prepandemic vaccine and antiviral strategies.

scholarly journals Next generation methodology for updating HA vaccines against emerging human seasonal influenza A(H3N2) viruses

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
James D. Allen ◽  
Ted M. Ross
Keyword(s):  
Influenza Virus ◽  
Immune Responses ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Influenza Viruses ◽  
Next Generation ◽  
Virus Infections ◽  
Wild Type ◽  
Influenza Hemagglutinin ◽  
H3n2 Influenza

AbstractWhile vaccines remain the best tool for preventing influenza virus infections, they have demonstrated low to moderate effectiveness in recent years. Seasonal influenza vaccines typically consist of wild-type influenza A and B viruses that are limited in their ability to elicit protective immune responses against co-circulating influenza virus variant strains. Improved influenza virus vaccines need to elicit protective immune responses against multiple influenza virus drift variants within each season. Broadly reactive vaccine candidates potentially provide a solution to this problem, but their efficacy may begin to wane as influenza viruses naturally mutate through processes that mediates drift. Thus, it is necessary to develop a method that commercial vaccine manufacturers can use to update broadly reactive vaccine antigens to better protect against future and currently circulating viral variants. Building upon the COBRA technology, nine next-generation H3N2 influenza hemagglutinin (HA) vaccines were designed using a next generation algorithm and design methodology. These next-generation broadly reactive COBRA H3 HA vaccines were superior to wild-type HA vaccines at eliciting antibodies with high HAI activity against a panel of historical and co-circulating H3N2 influenza viruses isolated over the last 15 years, as well as the ability to neutralize future emerging H3N2 isolates.

scholarly journals Use of failure modes and effects analysis to mitigate potential risks prior to implementation of an intravenous compounding technology

2021 ◽  
Author(s):  
Agnes Ann Feemster ◽  
Melissa Augustino ◽  
Rosemary Duncan ◽  
Anand Khandoobhai ◽  
Meghan Rowcliffe
Keyword(s):  
Medication Safety ◽  
Failure Modes ◽  
Risk Mitigation ◽  
New Technology ◽  
Hazard Index ◽  
Mitigation Strategies ◽  
Investigational Drug ◽  
Workflow Optimization ◽  
Proactive Approach ◽  
Risk Mitigation Strategies

Abstract Disclaimer In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose The purpose of this study was to identify potential failure points in a new chemotherapy preparation technology and to implement changes that prevent or minimize the consequences of those failures before they occur using the failure modes and effects analysis (FMEA) approach. Methods An FMEA was conducted by a team of medication safety pharmacists, oncology pharmacists and technicians, leadership from informatics, investigational drug, and medication safety services, and representatives from the technology vendor. Failure modes were scored using both Risk Priority Number (RPN) and Risk Hazard Index (RHI) scores. Results The chemotherapy preparation workflow was defined in a 41-step process with 16 failure modes. The RPN and RHI scores were identical for each failure mode because all failure modes were considered detectable. Five failure modes, all attributable to user error, were deemed to pose the highest risk. Mitigation strategies and system changes were identified for 2 failure modes, with subsequent system modifications resulting in reduced risk. Conclusion The FMEA was a useful tool for risk mitigation and workflow optimization prior to implementation of an intravenous compounding technology. The process of conducting this study served as a collaborative and proactive approach to reducing the potential for medication errors upon adoption of new technology into the chemotherapy preparation process.

A Low-Fidelity Stochastic Model of Viral Spread in Aircraft to Assess Risk Mitigation Strategies

2021 ◽  
Author(s):  
Leigh McCue
Keyword(s):  
Large Scale ◽  
Risk Mitigation ◽  
Mitigation Strategies ◽  
Traffic Network ◽  
Computationally Efficient ◽  
Passenger Compartment ◽  
Stochastic Effects ◽  
Viral Spread ◽  
Risk Mitigation Strategies ◽  
Baseline Health

Abstract The purpose of this work is to develop a computationally efficient model of viral spread that can be utilized to better understand influences of stochastic factors on a large-scale system - such as the air traffic network. A particle-based model of passengers and seats aboard a single-cabin 737-800 is developed for use as a demonstration of concept on tracking the propagation of a virus through the aircraft's passenger compartment over multiple flights. The model is sufficiently computationally efficient so as to be viable for Monte Carlo simulation to capture various stochastic effects, such as number of passengers, number of initially sick passengers, seating locations of passengers, and baseline health of each passenger. The computational tool is then exercised in demonstration for assessing risk mitigation of intervention strategies, such as passenger-driven cleaning of seating environments and elimination of middle seating.

scholarly journals Management of Cardiac Implantable Electrical Devices in Patients Undergoing Radiofrequency Ablation for Spine Pain: Physician Survey and Review of Guidelines

2020 ◽  
Vol 4;23 (7;4) ◽  
pp. E335-E342
Author(s):  
Jason Friedrich
Keyword(s):  
Decision Making ◽  
Chronic Pain ◽  
Radiofrequency Ablation ◽  
Joint Pain ◽  
Risk Mitigation ◽  
Narrative Review ◽  
Mitigation Strategies ◽  
Web Based ◽  
Electrical Devices ◽  
Risk Mitigation Strategies

Background: More patients with cardiac implantable electrical devices (CIEDs) are presenting to spine and pain practices for radiofrequency ablation (RFA) procedures for chronic pain. Although the potential for electromagnetic interference (EMI) affecting CIED function is known with RFA procedures, available guidelines do not specifically address CIED management for percutaneous RFA for zygapophyseal (z-joint) joint pain, and thus physician practice may vary. Objectives: To better understand current practices of physicians who perform RFA for chronic z-joint pain with respect to management of CIEDs. Perioperative CIED management guidelines are also reviewed to specifically address risk mitigation strategies for potential EMI created by ambulatory percutaneous spine RFA procedures. Study Design: Web-based provider survey and narrative review. Setting: Multispecialty pain clinic, academic medical center. Methods: A web-based survey was created using Research Electronic Data Capture (REDCap). A survey link was provided via e-mail to active members of the Spine Intervention Society (SIS), American Society of Regional Anesthesia and Pain Medicine, as well as distributed freely to community Pain Physicians and any receptive academic departments of PM&R or Anesthesiology. The narrative review summarizes pertinent case series, review articles, a SIS recommendation statement, and multi-specialty peri-operative guidelines as they relate specifically to spine RFA procedures. Results: A total of 197 clinicians participated in the survey from diverse clinical backgrounds, including anesthesiology, physical medicine and rehabilitation, radiology, neurosurgery, and neurology, with 81% reporting fellowship training. Survey responses indicate wide variability in provider management of CIEDs before, during, and after RFA for z-joint pain. Respondents indicated they would like more specific guidelines to aid in management and decision-making around CIEDs and spine RFA procedures. Literature review yielded several practice guidelines related to perioperative management of CIEDs, but no specific guideline for percutaneous spine RFA procedures. However, combining the risk mitigation strategies provided in these guidelines, with interventional pain physician clinical experience allows for reasonable management recommendations to aid in decision-making. Limitations: Although this manuscript can serve as a review of CIEDs and aid in management decisions in patients with CIEDs, it is not a clinical practice guideline. Conclusions: Practice patterns vary regarding CIED management in ambulatory spine RFA procedures. CIED presence is not a contraindication for spine RFA but does increase the complexity of a spine RFA procedure and necessitates some added precautions. Key words: Radiofrequency ablation, neurotomy, cardiac implantable electrical device, zygapophyseal joint, spondylosis, neck pain, low back pain, chronic pain

scholarly journals Restarting elective endoscopy safely amidst an evolving pandemic and the impact of patient perception

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Christopher Nguyen ◽  
Kevin T. Kline ◽  
Shehzad Merwat ◽  
Sheharyar Merwat ◽  
Gurinder Luthra ◽  
...  
Keyword(s):  
Risk Mitigation ◽  
Mitigation Strategies ◽  
Transmission Risk ◽  
Dynamic Monitoring ◽  
Successful Model ◽  
Outpatient Procedures ◽  
Risk Patients ◽  
Risk Mitigation Strategies ◽  
Spread Of Infection ◽  
The Impact

Abstract Background The COVID-19 pandemic has led to disruptions in elective and outpatient procedures. Guidance from the Centers for Medicare and Medicaid Services provided a framework for gradual reopening of outpatient clinical operations. As the infrastructure to restart endoscopy has been more clearly described, patient concerns regarding viral transmission during the procedure have been identified. Moreover, the efficacy of the measures in preventing transmission have not been clearly delineated. Methods We identified patients with pandemic-related procedure cancellations from 3/16/2020 to 4/20/2020. Patients were stratified into tier groups (1–4) by urgency. Procedures were performed using our hospital risk mitigation strategies to minimize transmission risk. Patients who subsequently developed symptoms or tested for COVID-19 were recorded. Results Among patients requiring emergent procedures, 57.14% could be scheduled at their originally intended interval. COVID-19 concerns represented the most common rescheduling barrier. No patients who underwent post-procedure testing were positive for COVID-19. No cases of endoscopy staff transmission were identified. Conclusions Non-COVID-19 related patient care during the pandemic is a challenging process that evolved with the spread of infection, requiring dynamic monitoring and protocol optimization. We describe our successful model for reopening endoscopy suites using a tier-based system for safe reintroduction of elective procedures while minimizing transmission to patients and staff. Important barriers included financial and transmission concerns that need to be addressed to enable the return to pre-pandemic utilization of elective endoscopic procedures.

scholarly journals Corporate Foreign Corrupt Practices and Director Liability

2014 ◽  
Vol 51 (3) ◽  
pp. 555
Author(s):  
Paul Blyschak
Keyword(s):  
Risk Mitigation ◽  
Civil Liability ◽  
Case Law ◽  
Corporate Law ◽  
Mitigation Strategies ◽  
Public Officials ◽  
Risk Mitigation Strategies ◽  
American Case ◽  
Director Liability

This article examines the various forms of potential liability faced by directors in their capacity as such in connection with corrupt practices engaged in by the corporations they serve. Although generally little discussed to date, Canadian directors do face potential civil liability associated with contraventions of the Corruption of Foreign Public Officials Act that are particular to their status as directors of a corporation. This article thus highlights this particular area of corporate law by reviewing both Canadian jurisprudence and American case law to decipher what lessons Canadian directors can learn in the absence of Canadian precedent similarly on point. Several key cases are highlighted and various risk mitigation strategies available to Canadian directors to guard against these potential liabilities are also discussed.

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