Aspirin therapy in patients with acute respiratory distress syndrome (ARDS) is associated with reduced intensive care unit mortality: a prospective analysis

INTRODUCTION: Acute respiratory distress syndrome (ARDS) is a common clinical syndrome with high mortality and long-term morbidity. To date there is no effective pharmacological therapy. Aspirin therapy has recently been shown to reduce the risk of developing ARDS, but the effect of aspirin on established ARDS is unknown.

METHODS: In a single large regional medical and surgical ICU between December 2010 and July 2012, all patients with ARDS were prospectively identified and demographic, clinical, and laboratory variables were recorded retrospectively. Aspirin usage, both pre-hospital and during intensive care unit (ICU) stay, was included. The primary outcome was ICU mortality. We used univariate and multivariate logistic regression analyses to assess the impact of these variables on ICU mortality.

RESULTS: In total, 202 patients with ARDS were included; 56 (28%) of these received aspirin either pre-hospital, in the ICU, or both. Using multivariate logistic regression analysis, aspirin therapy, given either before or during hospital stay, was associated with a reduction in ICU mortality (odds ratio (OR) 0.38 (0.15 to 0.96) P = 0.04). Additional factors that predicted ICU mortality for patients with ARDS were vasopressor use (OR 2.09 (1.05 to 4.18) P = 0.04) and APACHE II score (OR 1.07 (1.02 to 1.13) P = 0.01). There was no effect upon ICU length of stay or hospital mortality.

CONCLUSION: Aspirin therapy was associated with a reduced risk of ICU mortality. These data are the first to demonstrate a potential protective role for aspirin in patients with ARDS. Clinical trials to evaluate the role of aspirin as a pharmacological intervention for ARDS are needed.

Unexpected Role for Adaptive αβTh17 Cells in Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a devastating disorder characterized by increased alveolar permeability with no effective treatment beyond supportive care. Current mechanisms underlying ARDS focus on alveolar endothelial and epithelial injury caused by products of innate immune cells and platelets. However, the role of adaptive immune cells in ARDS remains largely unknown. In this study, we report that expansion of Ag-specific αβTh17 cells contributes to ARDS by local secretion of IL-17A, which in turn directly increases alveolar epithelial permeability. Mice with a highly restrictive defect in Ag-specific αβTh17 cells were protected from experimental ARDS induced by a single dose of endotracheal LPS. Loss of IL-17 receptor C or Ab blockade of IL-17A was similarly protective, further suggesting that IL-17A released by these cells was responsible for this effect. LPS induced a rapid and specific clonal expansion of αβTh17 cells in the lung, as determined by deep sequencing of the hypervariable CD3RβVJ region of the TCR. Our findings could be relevant to ARDS in humans, because we found significant elevation of IL-17A in bronchoalveolar lavage fluid from patients with ARDS, and rIL-17A directly increased permeability across cultured human alveolar epithelial monolayers. These results reveal a previously unexpected role for adaptive immune responses that increase alveolar permeability in ARDS and suggest that αβTh17 cells and IL-17A could be novel therapeutic targets for this currently untreatable disease.

Relationship between Azithromycin Susceptibility and Administration Efficacy for Nontypeable Haemophilus influenzae Respiratory Infection

Nontypeable Haemophilus influenzae (NTHI) is an opportunistic pathogen that is an important cause of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). COPD is an inflammatory disease of the airways, and exacerbations are acute inflammatory events superimposed on this background of chronic inflammation. Azithromycin (AZM) is a macrolide antibiotic with antibacterial and anti-inflammatory properties and a clinically proven potential for AECOPD prevention and management. Relationships between AZM efficacy and resistance by NTHI and between bactericidal and immunomodulatory effects on NTHI respiratory infection have not been addressed. In this study, we employed two pathogenic NTHI strains with different AZM susceptibilities (NTHI 375 [AZM susceptible] and NTHI 353 [AZM resistant]) to evaluate the prophylactic and therapeutic effects of AZM on the NTHI-host interplay. At the cellular level, AZM was bactericidal toward intracellular NTHI inside alveolar and bronchial epithelia and alveolar macrophages, and it enhanced NTHI phagocytosis by the latter cell type. These effects correlated with the strain MIC of AZM and the antibiotic dose. Additionally, the effect of AZM on NTHI infection was assessed in a mouse model of pulmonary infection. AZM showed both preventive and therapeutic efficacies by lowering NTHI 375 bacterial counts in lungs and bronchoalveolar lavage fluid (BALF) and by reducing histopathological inflammatory lesions in the upper and lower airways of mice. Conversely, AZM did not reduce bacterial loads in animals infected with NTHI 353, in which case a milder anti-inflammatory effect was also observed. Together, the results of this work link the bactericidal and anti-inflammatory effects of AZM and frame the efficacy of this antibiotic against NTHI respiratory infection.

Mesenchymal stromal cells for treatment of the acute respiratory distress syndrome: The beginning of the story

In spite of decades of research, the acute respiratory distress syndrome (ARDS) continues to have an unacceptably high mortality and morbidity. Mesenchymal stromal cells (MSCs) present a promising candidate for the treatment of this condition and have demonstrated benefit in preclinical models. MSCs, which are a topic of growing interest in many inflammatory disorders, have already progressed to early phase clinical trials in ARDS. While a number of their mechanisms of effect have been elucidated, a better understanding of the complex actions of these cells may pave the way for MSC modifications, which might enable more effective translation into clinical practice.

The Nature of Magnetoelectric Coupling in Pb(Zr,Ti)O3-Pb(Fe,Ta)O3

The coupling between magnetization and polarization in a room temperature multiferroic (Pb(Zr,Ti)O3–Pb(Fe,Ta)O3) is explored by monitoring changes in capacitance that occur when a magnetic field is applied in each of three orthogonal directions. Magnetocapacitance effects, consistent with P2M2 coupling, are strongest when fields are applied in the plane of the single crystal sheet investigated.

Neural dysfunction following respiratory viral infection as a cause of chronic cough hypersensitivity

Respiratory viral infections are a common cause of acute coughing, an irritating symptom for the patient and an important mechanism of transmission for the virus. Although poorly described, the inflammatory consequences of infection likely induce coughing by chemical (inflammatory mediator) or mechanical (mucous) activation of the cough-evoking sensory nerves that innervate the airway wall. For some individuals, acute cough can evolve into a chronic condition, in which cough and aberrant airway sensations long outlast the initial viral infection. This suggests that some viruses have the capacity to induce persistent plasticity in the neural pathways mediating cough. In this brief review we present the clinical evidence of acute and chronic neural dysfunction following viral respiratory tract infections and explore possible mechanisms by which the nervous system may undergo activation, sensitization and plasticity.

An audit of antimicrobial treatment of lower respiratory and urinary tract infections in a hospital setting

Objectives: To audit the quality of treatment of lower respiratory tract infections (LRTIs) and urinary tract infections (UTIs) and to identify targets for antibiotic stewardship. Methods: The audit involved collecting data on admitted patients, who were diagnosed with LRTIs or UTIs and subsequently received antibiotic treatment (January 2009-April 2009). Key findings: The percentage adherence rate for hospital antibiotic policy was 68.6% (24/35). Documentation of the CURB-65 score was found in 80% (16/20) of the patients' clinical notes, for which 46.2% (6/13) of patients were treated according to their CURB- 65 score. The percentages of delayed and missed doses for all antibiotics were 21.7% (254/1171) and 8.6% (101/1171), respectively. The percentage of patients switched from intravenous to oral antibiotics in accordance with the policy was 58.5% (31/53). The mean length of stay for patients switched in line with the guidelines was 6.9 days (range: 2-18 days) compared with 13.2 days (range: 4-28 days) for patients treated with intravenous antibiotics >24 h after the intravenous to oral switch criteria were fulfilled; this equates to on average an extra 6.3 days of hospitalisation (p=0.01). Conclusions: The study identified a number of targets for quality improvement including adherence to antibiotic policy, documentation of the CURB-65 score in patients' notes and treating patients accordingly, addressing the issue of missed and delayed doses, and maintaining adherence to the hospital intravenous-to-oral antibiotic switch policy. The findings suggest that the quality of antibiotic prescribing could be improved by measuring and addressing such performance indicators.

New methods for studying perception and action coupling

To study perception and action, Gibson advocated that “the laboratory must be like life” (Gibson, 1979, p. 3). In other words, the interactive relationship between an organism and his/her envi- ronment must be maintained so that the behavior observed in an experimental context mirrors, as closely as possible, the behavior observed in a realistic sport setting. The concept of repre- sentative design introduced by Brunswik in 1956 emphasized the need to have experimental tasks that allow the player to pick up perceptual information that specifies a property of the environment-actor system (Araújo et al., 2005; see also Chapter 24). In this chapter we will provide a brief overview of the methodologies used to study perception and action in sport and present, in some detail, the opportunities new methodologies such as immersive, interactive vir- tual reality can offer researchers in sport expertise.

72 Potential for airborne bacterial contamination in an outpatient respiratory clinic

Total Synthesis of the Potent HIF-1 Inhibitory Antitumor Natural Product, (8R)-Mycothiazole, via Baldwin–Lee CsF/CuI sp3–sp2-Stille Cross-Coupling. Confirmation of the Crews Reassignment

A convenient asymmetric total synthesis of the potent HIF-1 inhibitory antitumor natural product, (−)- or (+)-(8R)-mycothiazole (1), is described. Not only does our synthesis confirm the 2006 structural reassignment made by Crews (Crews, P., et al. J. Nat. Prod. 2006, 69, 145), it revises the [α]_D data previously reported for this molecule in MeOH from −13.7° to +42.3°. The newly developed route to (8R)-1 sets the C(8)–OH stereocenter via Sharpless AE/2,3-epoxy alcohol reductive ring opening and utilizes two Baldwin–Lee CsF/cat. CuI Stille cross-coupling reactions with vinylstannanes 8 and 3 to efficiently elaborate the C(1)–C(4) and C(14)–C(18) sectors.

Induction and antagonism of antiviral responses in respiratory syncytial virus-infected pediatric airway epithelium.

Airway epithelium is the primary target of many respiratory viruses. However, virus induction and antagonism of host responses by human airway epithelium remains poorly understood. To address this, we developed a model of respiratory syncytial virus (RSV) infection based on well- differentiated pediatric primary bronchial epithelial cell cultures (WD-PBECs) that mimics hallmarks of RSV disease in infants. RSV is the most important respiratory viral pathogen in young infants worldwide. We found that RSV induces a potent antiviral state in WD-PBECs that was mediated in part by secreted factors, including interferon lambda-1 (IFNλ1)/IL-29. In contrast, type I interferons were not detected following RSV infection of WD-PBECs., Interferon (IFN) responses in RSV-infected WD-PBECs reflected those in lower airway samples from RSV-hospitalized infants. In view of the prominence of IL-29, we determined whether recombinant IL-29 treatment of WD-PBECs before or after infection abrogated RSV replication. Interestingly, IL-29 demonstrated prophylactic, but not therapeutic, potential against RSV. The absence of therapeutic potential reflected effective RSV antagonism of IFN-mediated antiviral responses in infected cells. Our data are consistent with RSV non-structural proteins 1 and/or 2 perturbing the Jak-STAT signaling pathway, with concomitant reduced expression of antiviral effector molecules, such as MxA/B. Antagonism of Jak-STAT signaling was restricted to RSV-infected cells in WD-PBEC cultures. Importantly, our study provides the rationale to further explore IL-29 as a novel RSV prophylactic.