The coronavirus disease-19 pandemic (COVID-19), which appeared in China in December 2019 and rapidly spread throughout the world, has forced clinicians and scientists to take up extraordinary ...challenges. This unprecedented situation led to the inception of numerous fundamental research protocols and many clinical trials. It quickly became apparent that although COVID-19, in the vast majority of cases, was a benign disease, it could also develop a severe form with sometimes fatal outcomes. Cytokines are central to the pathophysiology of COVID-19; while some of them are beneficial (type-I interferon, interleukin-7), others appear detrimental (interleukin-1β, -6, and TNF-α) particularly in the context of the so-called cytokine storm. Yet another characteristic of the disease has emerged: concomitant immunodeficiency, notably involving impaired type-I interferon response, and lymphopenia. This review provides an overview of current knowledge on COVID-19 immunopathology. We discuss the defective type-I IFN response, the theoretical role of IL-7 to restore lymphocyte repertoire, as well as we mention the two patterns observed in severe COVID-19 (i.e. interleukin-1β-driven macrophage activation syndrome vs. interleukin-6-driven immune dysregulation). Next, reviewing current evidence drawn from clinical trials, we examine a number of cytokine and anti-cytokine therapies, including interleukin-1, -6, and TNF inhibitors, as well as less targeted therapies, such as corticosteroids, chloroquine, or JAK inhibitors.
•COVID-19 induces both impairment and hyperactivation of the immune system.•Early viral clearance by type-I IFN is a key to preventing further viral replication, T cell exhaustion, and cytokine storm.•Timely administration of treatments may reduce viral load and avoid hyperinflammation.
Patients treated with targeted temperature management (32 to 34°C) after cardiac arrest are at increased risk for early ventilator-associated pneumonia. In this multicenter trial, intravenous ...amoxicillin–clavulanate for 48 hours after cardiac arrest resulted in a lower incidence of early ventilator-associated pneumonia than placebo but did not affect ventilator-free days or mortality at day 28.
Sepsis is a syndrome which is defined as a dysregulated host response to infection leading to organ failure. Since it remains one of the leading causes of mortality worldwide, numerous drug ...candidates have already been tested, and continue to be developed, as potential adjunct therapies. Despite convincing mechanisms of action and robust pre-clinical data, almost all drug candidates in the field of sepsis have failed to demonstrate clinical efficacy in the past two decades. Accordingly, the development of new sepsis drugs has markedly decreased in the past few years. Nevertheless, thanks to a better understanding of sepsis pathophysiology and pathways, new promising drug candidates are currently being developed. Instead of a unique sepsis profile as initially suspected, various phenotypes have been characterised. This has resulted in the identification of multiple targets for new drugs together with relevant biomarkers, and a better understanding of the most appropriate time to intervention. Within the entire sepsis drugs portfolio, those targeting the immune response are probably the most promising. Monoclonal antibodies targeting either cytokines or infectious agents are undoubtedly part of the potential successful therapeutic classes to come.
Because of its resistance profiles, Pseudomonas aeruginosa remains probably one of the challenging bacteria responsible for ventilator-associated pneumonia in the ICU. Nevertheless, a much better ...understanding of its mechanism of virulence, such as the type 3 secretion system that can also impact on resistance, gives some opportunities for management improvement. The most promising approach is probably the production of monoclonal antibodies that enable not only more targeted treatments but also development of some early preemptive approaches at the time of colonization through real-time diagnosis.
We report on experimental and numerical implementations of devices based on the negative refraction of elastic guided waves, the so-called Lamb waves. Consisting in plates of varying thickness, these ...devices rely on the concept of complementary media, where a particular layout of negative index media can cloak an object with its anti-object or trap waves around a negative corner. The diffraction cancellation operated by negative refraction is investigated by means of laser ultrasound experiments. However, unlike original theoretical predictions, these intriguing wave phenomena remain, nevertheless, limited to the propagating component of the wave-field. To go beyond the diffraction limit, negative refraction is combined with the concept of metalens, a device converting the evanescent components of an object into propagating waves. The transport of an evanescent wave-field is then possible from an object plane to a far-field imaging plane. Twenty years after Pendry's initial proposal, this work thus paves the way towards an elastic superlens.
Staphylococcus aureus remains a common cause of ventilator-associated pneumonia, with little change in incidence over the past 15 years. We aimed to evaluate the efficacy of suvratoxumab, a ...monoclonal antibody targeting the α toxin, in reducing the incidence of S aureus pneumonia in patients in the intensive care unit (ICU) who are on mechanical ventilation.
We did a multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 2 pilot trial at 31 hospitals in Belgium, the Czech Republic, France, Germany, Greece, Hungary, Portugal, Spain, and Switzerland. Eligible patients were in the ICU, aged ≥18 years, were intubated and on mechanical ventilation, were positive for S aureus colonisation of the lower respiratory tract, as assessed by quantitative PCR (qPCR) analysis of endotracheal aspirate, and had not been diagnosed with new-onset pneumonia. Patients were excluded if they had confirmed or suspected acute ongoing staphylococcal disease; had received antibiotics for S aureus infection for more than 48 h within 72 h of randomisation; had a Clinical Pulmonary Infection Score of 6 or higher; had an acute physiology and chronic health evaluation II score of 25 or higher with a Glasgow coma scale (GCS) score of more than 5, or an acute physiology and chronic health evaluation II score of at least 30 with a GCS score of 5 or less; had a Sequential Organ Failure Assessment score of 9 or higher; or had active pulmonary disease that would impair the ability to diagnose pneumonia. Colonised patients were randomly assigned (1:1:1), by use of an interactive voice or web response system, to receive either a single intravenous infusion of suvratoxumab 2000 mg, suvratoxumab 5000 mg, or placebo. Randomisation was done in blocks of size four, stratified by country and by whether patients had received systemic antibiotics for S aureus infection. Patients, investigators, and study staff involved in the treatment or clinical evaluation of patients were masked to patient assignment. The primary efficacy endpoint was the incidence of S aureus pneumonia at 30 days, as determined by a masked independent endpoint adjudication committee, in all patients who received their assigned treatment (modified intention-to-treat ITT population). Primary safety endpoints were the incidence of treatment-emergent adverse events at 30 days, 90 days, and 190 days after treatment, and the incidence of treatment-emergent serious adverse events, adverse events of special interest, and new-onset chronic disease at 190 days after treatment. All primary safety endpoints were assessed in the modified ITT population. This trial is registered with ClinicalTrials.gov (NCT02296320) and the EudraCT database (2014-001097-34).
Between Oct 10, 2014, and April 1, 2018, 767 patients were screened, of whom 213 patients with confirmed S aureus colonisation of the lower respiratory tract were randomly assigned to the suvratoxumab 2000 mg group (n=15), the suvratoxumab 5000 mg group (n=96), or the placebo group (n=102). Two patients in the placebo group did not receive treatment after randomisation because their clinical conditions changed and they no longer met the eligibility criteria for dosing. As adjudicated by the data monitoring committee at an interim analysis, the suvratoxumab 2000 mg group was discontinued on the basis of predefined pharmacokinetic criteria. At 30 days after treatment, 17 (18%) of 96 patients in the suvratoxumab 5000 mg group and 26 (26%) of 100 patients in the placebo group had developed S aureus pneumonia (relative risk reduction 31·9% 90% CI −7·5 to 56·8, p=0·17). The incidence of treatment-emergent adverse events at 30 days were similar between the suvratoxumab 5000 mg group (87 91%) and the placebo group (90 90%). The incidence of treatment-emergent serious adverse events at 30 days were also similar between the suvratoxumab 5000 mg group (36 38%) and the placebo group (32 32%). No significant difference in the incidence of treatment-emergent adverse events between the two groups at 90 days (89 93% in the suvratoxumab 5000 mg group vs 92 92% in the placebo group) and at 190 days (93 94% vs 93 93%) was observed. 40 (40%) patients in the placebo group and 50 (52%) in the suvratoxumab 5000 mg group had a serious adverse event at 190 days. In the suvratoxumab 5000 mg group, one (1%) patient reported at least one treatment-emergent serious adverse event related to treatment, two (2%) patients reported an adverse event of special interest, and two (2%) reported a new-onset chronic disease.
In patients in the ICU receiving mechanical ventilation with qPCR-confirmed S aureus colonisation of the lower respiratory tract, the incidence of S aureus pneumonia at 30 days was not significantly lower following treatment with 5000 mg suvratoxumab than with placebo. Despite these negative results, monoclonal antibodies still represent one promising therapeutic option to reduce antibiotic consumption that require further exploration and studies.
AstraZeneca, with support from the Innovative Medicines Initiative Joint Undertaking.
The Sequential Organ Failure Assessment or SOFA score was developed to assess the acute morbidity of critical illness at a population level and has been widely validated as a tool for this purpose ...across a range of healthcare settings and environments.In recent years, the SOFA score has become extensively used in a range of other applications. A change in the SOFA score of 2 or more is now a defining characteristic of the sepsis syndrome, and the European Medicines Agency has accepted that a change in the SOFA score is an acceptable surrogate marker of efficacy in exploratory trials of novel therapeutic agents in sepsis. The requirement to detect modest serial changes in a patients' SOFA score therefore means that increased clarity on how the score should be assessed in different circumstances is required.This review explores the development of the SOFA score, its applications and the challenges associated with measurement. In addition, it proposes guidance designed to facilitate the consistent and valid assessment of the score in multicentre sepsis trials involving novel therapeutic agents or interventions.ConclusionThe SOFA score is an increasingly important tool in defining both the clinical condition of the individual patient and the response to therapies in the context of clinical trials. Standardisation between different assessors in widespread centres is key to detecting response to treatment if the SOFA score is to be used as an outcome in sepsis clinical trials.
We demonstrate a vapor-cell atomic-clock prototype based on a continuous-wave interrogation and double-modulation coherent population trapping (DM-CPT) technique. The DM-CPT technique uses a ...synchronous modulation of polarization and the relative phase of a bichromatic laser beam in order to increase the number of atoms trapped in a dark state, i.e., a nonabsorbing state. The narrow resonance, observed in the transmission of a Cs vapor cell, is used as a narrow frequency discriminator in an atomic clock. A detailed characterization of the CPT resonance versus numerous parameters is reported. A short-term fractional-frequency stability of 3.2×10−13τ−1/2 up to a 100-s averaging time is measured. These performances are more than one order of magnitude better than industrial Rb clocks and are comparable to those of the best laboratory-prototype vapor-cell clocks. The noise-budget analysis shows that the short- and midterm frequency stability is mainly limited by the power fluctuations of the microwave used to generate the bichromatic laser. These preliminary results demonstrate that the DM-CPT technique is well suited for the development of a high-performance atomic clock, with the potential compact and robust setup due to its linear architecture. This clock could find future applications in industry, telecommunications, instrumentation, or global navigation satellite systems.
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