Functional genomics screens reveal a role for TBC1D24 and SV2B in antibody-dependent enhancement of dengue virus infection.

Dengue virus (DENV) can hijack non-neutralizing IgG antibodies to facilitate its uptake into target cells expressing Fc gamma receptors (FcgR) - a process known as antibody-dependent enhancement (ADE) of infection. Beyond a requirement for FcgR, host dependency factors for this non-canonical infection route remain unknown. To identify cellular factors exclusively required for ADE, here, we performed CRISPR knockout screens in an system permissive to infection only in the presence of IgG antibodies.

Defining the impact of flavivirus envelope protein glycosylation site mutations on sensitivity to broadly neutralizing antibodies.

Antibodies targeting an envelope dimer epitope (EDE) cross-neutralize Zika virus (ZIKV) and dengue virus (DENV) and have thus inspired an epitope-focused vaccine design. There are two EDE antibody subclasses (EDE1, EDE2) distinguished by their dependence on viral envelope protein -linked glycosylation at position N153 (DENV) or N154 (ZIKV) for binding. Here, we determined how envelope glycosylation site mutations affect by EDE and other broadly neutralizing antibodies.

The effect of single mutations in Zika virus envelope on escape from broadly neutralizing antibodies.

The wide endemic range of mosquito-vectored flaviviruses-such as Zika virus and dengue virus serotypes 1-4-places hundreds of millions of people at risk of infection every year. Despite this, there are no widely available vaccines, and treatment of severe cases is limited to supportive care. An avenue toward development of more widely applicable vaccines and targeted therapies is the characterization of monoclonal antibodies that broadly neutralize all these viruses.

Single B cell transcriptomics identifies multiple isotypes of broadly neutralizing antibodies against flaviviruses.

Sequential dengue virus (DENV) infections often generate neutralizing antibodies against all four DENV serotypes and sometimes, Zika virus. Characterizing cross-flavivirus broadly neutralizing antibody (bnAb) responses can inform countermeasures that avoid enhancement of infection associated with non-neutralizing antibodies. Here, we used single cell transcriptomics to mine the bnAb repertoire following repeated DENV infections.

The effect of single mutations in Zika virus envelope on escape from broadly neutralizing antibodies.

Zika virus and dengue virus are co-circulating flaviviruses with a widespread endemic range. Eliciting broad and potent neutralizing antibodies is an attractive goal for developing a vaccine to simultaneously protect against these viruses. However, the capacity of viral mutations to confer escape from broadly neutralizing antibodies remains undescribed, due in part to limited throughput and scope of traditional approaches.

Single B cell transcriptomics identifies multiple isotypes of broadly neutralizing antibodies against flaviviruses.

Sequential dengue virus (DENV) infections often generate neutralizing antibodies against all four DENV serotypes and sometimes, Zika virus. Characterizing cross-flavivirus broadly neutralizing antibody (bnAb) responses can inform countermeasure strategies that avoid infection enhancement associated with non-neutralizing antibodies. Here, we used single cell transcriptomics to mine the bnAb repertoire following secondary DENV infection.

The identification of needs and development of best practice guidance for the psychological support of frontline healthcare workers during and after COVID-19: A protocol for the FLoWS project.

Recent estimates suggest that up to 34% of frontline workers in healthcare (FLWs) at the forefront of the COVID-19 pandemic response are reporting elevated symptoms of psychological distress due to resource constraints, ineffective treatments, and concerns about self-contamination. However, little systematic research has been carried out to assess the mental health needs of FLWs in Europe, or the extent of psychological suffering in FLWs within different European countries of varying outbreak severity. Accordingly, this project will employ a mixed-methods approach over three work packages to develop best-practice guidelines for alleviating psychological distress in FLWs during the different phases of the pandemic.

Rapid development of interprofessional in situ simulation-based training in response to the COVID-19 outbreak in a tertiary-level hospital in Ireland: initial response and lessons for future disaster preparation.

Introduction: The first case of COVID-19 in Ireland was diagnosed on 29 February 2020. Within the same week, our Department of Anaesthesia and Critical Care at University Hospital Galway began to tackle the educational challenge by developing an  in situ interprofessional simulation programme to prepare staff for the impending outbreak.

Principles And Approaches Used For Simulation-based Training: We describe principles applied to identify core educational and system engineering objectives to prepare healthcare workers (HCWs) for infection control, personal and psychological safety, technical and crisis resource management skills.

Simulation as a toolkit-understanding the perils of blood transfusion in a complex health care environment.

Background: Administration of blood is a complex process requiring vigilance and effective teamwork. Despite strict policies and training on blood administration, errors still occur and can lead to mistransfusion with adverse patient outcomes. We used an in situ simulated scenario within an operating room (OR) to identify weaknesses in the current process and hazards that could contribute to mistransfusion.

Permissive hypercapnia: what to remember.

Purpose Of Review: Hypercapnia is a central component of diverse respiratory disorders, while 'permissive hypercapnia' is frequently used in ventilatory strategies for patients with severe respiratory failure. This review will present data from recent studies relating to hypercapnia, focusing on issues that are of importance to anesthesiologists caring for the surgical and/or critically ill patient.

Recent Findings: Protective ventilatory strategies involving permissive hypercapnia are widely used in patients with severe respiratory failure, particularly in acute respiratory distress syndrome, status asthmaticus, chronic obstructive pulmonary disease and neonatal respiratory failure.

Hypercapnic acidosis attenuates ventilation-induced lung injury by a nuclear factor-κB-dependent mechanism.

Objectives: Hypercapnic acidosis protects against ventilation-induced lung injury. We wished to determine whether the beneficial effects of hypercapnic acidosis in reducing stretch-induced injury were mediated via inhibition of nuclear factor-κB, a key transcriptional regulator in inflammation, injury, and repair.

Design: Prospective randomized animal study.

Evolution of the inflammatory and fibroproliferative responses during resolution and repair after ventilator-induced lung injury in the rat.

Background: The time course and mechanisms of resolution and repair, and the potential for fibrosis following ventilation-induced lung injury (VILI), are unclear. We sought to examine the pattern of inflammation, injury, repair, and fibrosis following VILI.

Methods: Sixty anesthetized rats were subject to high-stretch; low-stretch, or sham ventilation, and randomly allocated to undergo periods of recovery of 6, 24, 48, and 96 h, and 7 and 14 days.

Overexpression of pulmonary extracellular superoxide dismutase attenuates endotoxin-induced acute lung injury.

Purpose: Superoxide is produced by activated neutrophils during the inflammatory response to stimuli such as endotoxin, can directly or indirectly injure host cells, and has been implicated in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). We wished to determine the potential for pulmonary overexpression of the extracellular isoform of superoxide dismutase (EC-SOD) to reduce the severity of endotoxin-induced lung injury.

Methods: Animals were randomly allocated to undergo intratracheal instillation of (1) surfactant alone (vehicle); (2) adeno-associated virus (AAV) vectors containing a null transgene (AAV-null); and (3) adeno-associated virus vectors containing the EC-SOD transgene (AAV-EC-SOD) and endotoxin was subsequently administered intratracheally.

Clinical review: gene-based therapies for ALI/ARDS: where are we now?

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) confer substantial morbidity and mortality, and have no specific therapy. The accessibility of the distal lung epithelium via the airway route, and the relatively transient nature of ALI/ARDS, suggest that the disease may be amenable to gene-based therapies. Ongoing advances in our understanding of the pathophysiology of ALI/ARDS have revealed multiple therapeutic targets for gene-based approaches.

Hypercapnia and acidosis in sepsis: a double-edged sword?

Acute respiratory distress syndrome is a devastating disease that causes substantial morbidity and mortality. Mechanical ventilation can worsen lung injury, whereas ventilatory strategies that reduce lung stretch, resulting in a "permissive" hypercapnic acidosis (HCA), improve outcome. HCA directly reduces nonsepsis-induced lung injury in preclinical models and, therefore, has therapeutic potential in these patients.

Differential effects of buffered hypercapnia versus hypercapnic acidosis on shock and lung injury induced by systemic sepsis.

Background: Acute hypercapnic acidosis protects against lung injury caused by nonseptic insults and after both pulmonary and systemic sepsis. The authors wished to dissect the contribution of the acidosis versus hypercapnia per se to the effects of hypercapnic acidosis on the hemodynamic profile and severity of lung injury induced by systemic sepsis.

Methods: In the hypercapnic acidosis series, adult male Sprague-Dawley rats were randomized to normocapnia or hypercapnic acidosis-produced by adding 5% carbon dioxide to the inspired gas-and cecal ligation and puncture performed.

Hypercapnic acidosis attenuates shock and lung injury in early and prolonged systemic sepsis.

Objective: To investigate whether acute hypercapnic acidosis--induced by adding CO2 to inspired gas--would protect against severe systemic sepsis-induced lung and systemic organ injury resulting from cecal ligation and puncture. Acute hypercapnic acidosis protects against lung injury after both nonseptic and early pneumonia-induced lung injury. In contrast, prolonged hypercapnia worsens pneumonia-induced lung injury.