Sepsis - thoughtful management for the non-expert

Sepsis is a common and often devastating medical emergency with a high mortality rate and, in many survivors, long-term morbidity. It is defi ned as the dysregulated host response to infection resulting in organ dysfunction, and its incidence is increasing as the population ages. However, it is a treatable and potentially reversible condition, especially if identifi ed and treated promptly. A sound understanding of sepsis is crucial for optimal care. Although general guidelines are available for management, here we provide a foundation of understanding to encourage thoughtful, personalised management of sepsis during the acute phase. We provide an overview of the epidemiology, the new Sepsis-3 defi nitions, pathophysiology, clinical presentations, and investigation and management of sepsis for the non-expert

CD14+ CD15- HLA-DR- myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure.

OBJECTIVE: Immune paresis in patients with acute-on-chronic liver failure (ACLF) accounts for infection susceptibility and increased mortality. Immunosuppressive mononuclear CD14+HLA-DR- myeloid-derived suppressor cells (M-MDSCs) have recently been identified to quell antimicrobial responses in immune-mediated diseases. We sought to delineate the function and derivation of M-MDSC in patients with ACLF, and explore potential targets to augment antimicrobial responses. DESIGN: Patients with ACLF (n=41) were compared with healthy subjects (n=25) and patients with cirrhosis (n=22) or acute liver failure (n=30). CD14+CD15-CD11b+HLA-DR- cells were identified as per definition of M-MDSC and detailed immunophenotypic analyses were performed. Suppression of T cell activation was assessed by mixed lymphocyte reaction. Assessment of innate immune function included cytokine expression in response to Toll-like receptor (TLR-2, TLR-4 and TLR-9) stimulation and phagocytosis assays using flow cytometry and live cell imaging-based techniques. RESULTS: Circulating CD14+CD15-CD11b+HLA-DR- M-MDSCs were markedly expanded in patients with ACLF (55% of CD14+ cells). M-MDSC displayed immunosuppressive properties, significantly decreasing T cell proliferation (p=0.01), producing less tumour necrosis factor-alpha/interleukin-6 in response to TLR stimulation (all p<0.01), and reduced bacterial uptake of Escherichia coli (p<0.001). Persistently low expression of HLA-DR during disease evolution was linked to secondary infection and 28-day mortality. Recurrent TLR-2 and TLR-4 stimulation expanded M-MDSC in vitro. By contrast, TLR-3 agonism reconstituted HLA-DR expression and innate immune function ex vivo. CONCLUSION: Immunosuppressive CD14+HLA-DR- M-MDSCs are expanded in patients with ACLF. They were depicted by suppressing T cell function, attenuated antimicrobial innate immune responses, linked to secondary infection, disease severity and prognosis. TLR-3 agonism reversed M-MDSC expansion and innate immune function and merits further evaluation as potential immunotherapeutic agent

Mothers’ and fathers’ views on the importance of play for their children’s development: gender differences, academic activities, and the parental role

YesBackground: Play is a main driver of children’s cognitive and social development and is crucial for educational success (Ginsburg, 2007). In recent years however, parents and schools are under pressure to prioritise academic targets over play. Aims: The current research investigated parents’ views about three aspects of their children’s play and academic activities. Sample: Predominantly highly educated UK parents (109 mothers and 49fathers) were recruited via social media. Method: Participants were asked to complete an amended online version of the Preschool Play and Learning Questionnaire (Parmar, Harkness, & Super, 2004). The questionnaire consisted of 25 items covering three themes: the importance of play for children’s development, the importance of academic activities, and the importance of parents’ role in their children’s development. The independent variables were the gender of the parent, the gender of their child, and the age group of their child (4 to 7 years, or 8 to 11 years). Results: Parents rated play higher than academic activities or their own roles, but the difference was not noteworthy. However, fathers rated academic activities and the parents’ role significantly higher than mothers did. In addition, parents of girls rated academic activities and their own role, significantly higher than parents of boys. Conclusions: The findings of the current research highlight gender divisions between parents and towards boys and girls regarding the importance of education. Gender roles appear to influence the way parents think about the academic activities their children partake in

Selective mitochondrial antioxidant MitoTEMPO reduces renal dysfunction and systemic inflammation in experimental sepsis in rats

BACKGROUND: Excess mitochondrial reactive oxygen species (mROS) in sepsis is associated with organ failure, in part by generating inflammation through the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. We determined the impact of a mitochondrial-targeted antioxidant (MitoTEMPO) on mitochondrial dysfunction in renal proximal tubular epithelial cells, peritoneal immune cell function ex vivo, and organ dysfunction in a rat model of sepsis. METHODS: The effects of MitoTEMPO were assessed ex vivo using adenosine triphosphate and lipopolysaccharide-stimulated rat peritoneal immune cells and fresh rat kidney slices exposed to serum from septic rats. We assessed mROS production and phagocytotic capacity (flow cytometry), mitochondrial functionality (multiphoton imaging, respirometry), and NLRP3 inflammasome activation in cell culture. The effect of MitoTEMPO on organ dysfunction was evaluated in a rat model of faecal peritonitis. RESULTS: MitoTEMPO decreased septic serum-induced mROS (P0.05). In vivo, compared with untreated septic animals, MitoTEMPO reduced systemic IL-1β (P=0.01), reduced renal oxidative stress as determined by urine isoprostane levels (P=0.04), and ameliorated renal dysfunction (reduced serum urea (P<0.001) and creatinine (P=0.05). CONCLUSIONS: Reduction of mROS by a mitochondria-targeted antioxidant reduced IL-1β, and protected mitochondrial, cellular, and organ functionality after septic insults

High-altitude UAS pseudo-satellites: architecture for end-to-end military communications

High-Altitude Pseudo-Satellites (HAPS) have been identified as a potential option to either supplement or replace various military communications services. A network of HAPS aircraft operating at an altitude of 20km offers localized, high performance services to military operations. The intention of this work is to investigate whether a network of HAPS (specifically Airbus’ Zephyr S platform) is preferable to that of standard military communications infrastructure. Individual technologies were not studied directly, but rather the overall services were analyzed. This study will not replace services one-for-one, but rather investigate how HAPS can augment capabilities of current infrastructure. This need for supplementation of services may arise from increased service demand, or in the case of emergency, where other systems may be compromised. A particular emphasis is placed on command and control (C2) of the aircraft, and how this can be harnessed to produce the required communications network

X-Ray Specular Reflection Studies of Silicon Coated by Organic Monolayers (Alkylsiloxanes)

X-ray specular reflectivity has been used to characterize the structure of silicon–silicon-oxide surfaces coated with chemisorbed hydrocarbon monolayer films (alkylsiloxanes). Using synchrotron radiation the reflectivity was followed over 9 orders of magnitude, from grazing incidence to an incident angle of φ≊6.5°, or q=(4π/λ)sin(φ)=0.8 Å-1, allowing a spatial resolution of features approximately π/0.8≊4.0 Å along the surface normal. Analysis was performed by fitting the data to reflectivities calculated from models of the surface electron density and by calculating Patterson functions directly from the data. Although the measured reflectivities could be equally well described by different sets of model parameters, the electron densities calculated from these different parameters were remarkably alike. Inspection of the electron densities allowed identification of a layer of SiO2 (≊17-Å thick), a layer of head-group region where the alkylsiloxane adsorbs to the SiO2, and the hydrocarbon layer. Fitting the data also required that the various interfaces have different widths. The fact that the same local hydrocarbon density of 0.85 g/cm3 was observed for both fully formed and partially formed monolayers with alkane chains of varying length excluded a model in which the partially formed monolayer was made up of separated islands of well-formed monolayers. Measurements before and after chemical reaction of a monolayer in which the alkyl chain was terminated by an olefinic group demonstrated the ability to use x-ray reflectivity to characterize chemical changes. The effects of radiation damage on these types of measurements are described.Engineering and Applied Science

Intravenous Oncolytic Vaccinia Virus Therapy Results in a Differential Immune Response between Cancer Patients

Pexa-Vec is an engineered Wyeth-strain vaccinia oncolytic virus (OV), which has been tested extensively in clinical trials, demonstrating enhanced cytotoxic T cell infiltration into tumours following treatment. Favourable immune consequences to Pexa-Vec include the induction of an interferon (IFN) response, followed by inflammatory cytokine/chemokine secretion. This promotes tumour immune infiltration, innate and adaptive immune cell activation and T cell priming, culminating in targeted tumour cell killing, i.e., an immunologically ‘cold’ tumour microenvironment is transformed into a ‘hot’ tumour. However, as with all immunotherapies, not all patients respond in a uniformly favourable manner. Our study herein, shows a differential immune response by patients to intravenous Pexa-Vec therapy, whereby some patients responded to the virus in a typical and expected manner, demonstrating a significant IFN induction and subsequent peripheral immune activation. However, other patients experienced a markedly subdued immune response and appeared to exhibit an exhausted phenotype at baseline, characterised by higher baseline immune checkpoint expression and regulatory T cell (Treg) levels. This differential baseline immunological profile accurately predicted the subsequent response to Pexa-Vec and may, therefore, enable the development of predictive biomarkers for Pexa-Vec and OV therapies more widely. If confirmed in larger clinical trials, these immunological biomarkers may enable a personalised approach, whereby patients with an exhausted baseline immune profile are treated with immune checkpoint blockade, with the aim of reversing immune exhaustion, prior to or alongside OV therapy